Pharmaceutical composition, methods for treating and uses thereof

ABSTRACT

The invention relates to the treatment or prevention of one or more conditions selected from type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance and hyperglycemia using a SGLT-2 inhibitor. In addition the present invention relates to methods for preventing or treating of metabolic disorders and related conditions.

This application is a Continuation of U.S. patent application Ser. No.15/286,017 filed on Oct. 5, 2016, which is a Continuation of U.S. patentapplication Ser. No. 15/046,653 filed on Feb. 18, 2016, which is aContinuation of U.S. patent application Ser. No. 14/046,109 filed onOct. 4, 2013, which is a Continuation of U.S. patent application Ser.No. 13/439,324 filed on Apr. 4, 2012, which is a Continuation of U.S.patent application Ser. No. 12/704,062 filed on Feb. 11, 2010, whichclaims benefit from U.S. Provisional Application No. 61/152,318, filedon Feb. 13, 2009, the content of which are incorporated herein in theirentireties.

TECHNICAL FIELD OF THE INVENTION

The invention relates to a pharmaceutical composition comprising anSGLT2-inhibitor as described hereinafter which is suitable in thetreatment or prevention of one or more conditions selected from type 1diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance,impaired fasting blood glucose and hyperglycemia inter alia.

Furthermore the invention relates to methods

-   -   for preventing, slowing progression of, delaying, or treating a        metabolic disorder;    -   for improving glycemic control and/or for reducing of fasting        plasma glucose, of postprandial plasma glucose and/or of        glycosylated hemoglobin HbA1c;    -   for preventing, slowing, delaying or reversing progression from        impaired glucose tolerance, impaired fasting blood glucose,        insulin resistance and/or from metabolic syndrome to type 2        diabetes mellitus;    -   for preventing, slowing progression of, delaying or treating of        a condition or disorder selected from the group consisting of        complications of diabetes mellitus;    -   for reducing body weight and/or body fat, or preventing an        increase in body weight and/or body fat, or facilitating a        reduction in body weight and/or body fat;    -   for preventing or treating the degeneration of pancreatic beta        cells and/or for improving and/or restoring the functionality of        pancreatic beta cells and/or restoring the functionality of        pancreatic insulin secretion;    -   for preventing, slowing, delaying or treating diseases or        conditions attributed to an abnormal accumulation of ectopic        fat;    -   maintaining and/or improving the insulin sensitivity and/or for        treating or preventing hyperinsulinemia and/or insulin        resistance;    -   for preventing, slowing progression of, delaying, or treating        new onset diabetes after transplantation (NODAT) and/or        post-transplant metabolic syndrome (PTMS);    -   for preventing, delaying, or reducing NODAT and/or PTMS        associated complications including micro- and macrovascular        diseases and events, graft rejection, infection, and death;    -   for treating hyperuricemia and hyperuricemia associated        conditions;    -   for treating or preventing kidney stones;    -   for treating hyponatremia; in patients in need thereof        characterized in that a pharmaceutical composition comprising an        SGLT2 inhibitor as defined hereinafter is administered.

In addition the present invention relates to the use of an SGLT2inhibitor for the manufacture of a medicament for use in a method asdescribed hereinbefore and hereinafter.

The invention also relates to a use of a pharmaceutical compositionaccording to this invention for the manufacture of a medicament for usein a method as described hereinbefore and hereinafter.

BACKGROUND OF THE INVENTION

Type 2 diabetes is an increasingly prevalent disease that due to a highfrequency of complications leads to a significant reduction of lifeexpectancy. Because of diabetes-associated microvascular complications,type 2 diabetes is currently the most frequent cause of adult-onset lossof vision, renal failure, and amputations in the industrialized world.In addition, the presence of type 2 diabetes is associated with a two tofive fold increase in cardiovascular disease risk.

After long duration of disease, most patients with type 2 diabetes willeventually fail on oral therapy and become insulin dependent with thenecessity for daily injections and multiple daily glucose measurements.

The UKPDS (United Kingdom Prospective Diabetes Study) demonstrated thatintensive treatment with metformin, sulfonylureas or insulin resulted inonly a limited improvement of glycemic control (difference inHbA1c˜0.9%). In addition, even in patients within the intensivetreatment arm glycemic control deteriorated significantly over time andthis was attributed to deterioration of β-cell function. Importantly,intensive treatment was not associated with a significant reduction inmacrovascular complications, i.e. cardiovascular events. Therefore manypatients with type 2 diabetes remain inadequately treated, partlybecause of limitations in long term efficacy, tolerability and dosinginconvenience of existing antihyperglycemic therapies.

Oral antidiabetic drugs conventionally used in therapy (such as e.g.first- or second-line, and/or mono- or (initial or add-on) combinationtherapy) include, without being restricted thereto, metformin,sulphonylureas, thiazolidinediones, glinides and a-glucosidaseinhibitors.

The high incidence of therapeutic failure is a major contributor to thehigh rate of long-term hyperglycemia-associated complications or chronicdamages (including micro- and macrovascular complications such as e.g.diabetic nephrophathy, retinopathy or neuropathy, or cardiovascularcomplications) in patients with type 2 diabetes.

Therefore, there is an unmet medical need for methods, medicaments andpharmaceutical compositions with a good efficacy with regard to glycemiccontrol, with regard to disease-modifying properties and with regard toreduction of cardiovascular morbidity and mortality while at the sametime showing an improved safety profile.

SGLT2 inhibitors inhibitors represent a novel class of agents that arebeing developed for the treatment or improvement in glycemic control inpatients with type 2 diabetes. Glucopyranosyl-substituted benzenederivative are described in the prior art as SGLT2 inhibitors, forexample in WO 01/27128, WO 03/099836, WO 2005/092877, WO 2006/034489, WO2006/064033, WO 2006/117359, WO 2006/117360, WO 2007/025943, WO2007/028814, WO 2007/031548, WO 2007/093610, WO 2007/128749, WO2008/049923, WO 2008/055870, WO 2008/055940. Theglucopyranosyl-substituted benzene derivatives are proposed as inducersof urinary sugar excretion and as medicaments in the treatment ofdiabetes.

Renal filtration and reuptake of glucose contributes, among othermechanisms, to the steady state plasma glucose concentration and cantherefore serve as an antidiabetic target. Reuptake of filtered glucoseacross epithelial cells of the kidney proceeds via sodium-dependentglucose cotransporters (SGLTs) located in the brush-border membranes inthe tubuli along the sodium gradient. There are at least 3 SGLT isoformsthat differ in their expression pattern as well as in theirphysico-chemical properties. SGLT2 is exclusively expressed in thekidney, whereas SGLT1 is expressed additionally in other tissues likeintestine, colon, skeletal and cardiac muscle. SGLT3 has been found tobe a glucose sensor in interstitial cells of the intestine without anytransport function. Potentially, other related, but not yetcharacterized genes, may contribute further to renal glucose reuptake.Under normoglycemia, glucose is completely reabsorbed by SGLTs in thekidney, whereas the reuptake capacity of the kidney is saturated atglucose concentrations higher than 10 mM, resulting in glucosuria(“diabetes mellitus”). This threshold concentration can be decreased bySGLT2-inhibition. It has been shown in experiments with the SGLTinhibitor phlorizin that SGLT-inhibition will partially inhibit thereuptake of glucose from the glomerular filtrate into the blood leadingto a decrease in blood glucose concentrations and to glucosuria.

Aim of the Present Invention

The aim of the present invention is to provide a pharmaceuticalcomposition and method for preventing, slowing progression of, delayingor treating a metabolic disorder, in particular of type 2 diabetesmellitus.

A further aim of the present invention is to provide a pharmaceuticalcomposition and method for improving glycemic control in a patient inneed thereof, in particular in patients with type 2 diabetes mellitus.

Another aim of the present invention is to provide a pharmaceuticalcomposition and method for improving glycemic control in a patient withinsufficient glycemic control.

Another aim of the present invention is to provide a pharmaceuticalcomposition and method for preventing, slowing or delaying progressionfrom impaired glucose tolerance (IGT), impaired fasting blood glucose(IFG), insulin resistance and/or metabolic syndrome to type 2 diabetesmellitus.

Yet another aim of the present invention is to provide a pharmaceuticalcomposition and method for preventing, slowing progression of, delayingor treating of a condition or disorder from the group consisting ofcomplications of diabetes mellitus.

A further aim of the present invention is to provide a pharmaceuticalcomposition and method for reducing the weight or preventing an increaseof the weight in a patient in need thereof.

Another aim of the present invention is to provide a pharmaceuticalcomposition with a high efficacy for the treatment of metabolicdisorders, in particular of diabetes mellitus, impaired glucosetolerance (IGT), impaired fasting blood glucose (IFG), and/orhyperglycemia, which has good to very good pharmacological and/orpharmacokinetic and/or physicochemical properties.

Further aims of the present invention become apparent to the one skilledin the art by description hereinbefore and in the following and by theexamples.

SUMMARY OF THE INVENTION

Within the scope of the present invention it has now surprisingly beenfound that a pharmaceutical composition comprising a SGLT2 inhibitor asdefined hereinafter can advantageously be used for preventing, slowingprogression of, delaying or treating a metabolic disorder, in particularfor improving glycemic control in patients. This opens up newtherapeutic possibilities in the treatment and prevention of type 2diabetes mellitus, overweight, obesity, complications of diabetesmellitus and of neighboring disease states.

Therefore, in a first aspect the present invention provides a method forpreventing, slowing the progression of, delaying or treating a metabolicdisorder selected from the group consisting of type 1 diabetes mellitus,type 2 diabetes mellitus, impaired glucose tolerance (IGT), impairedfasting blood glucose (IFG), hyperglycemia, postprandial hyperglycemia,overweight, obesity, metabolic syndrome and gestational diabetes in apatient in need thereof characterized in that an SGLT2 inhibitor asdefined hereinbefore and hereinafter is administered to the patient.

According to another aspect of the invention, there is provided a methodfor improving glycemic control and/or for reducing of fasting plasmaglucose, of postprandial plasma glucose and/or of glycosylatedhemoglobin HbA1c in a patient in need thereof characterized in that anSGLT2 inhibitor as defined hereinbefore and hereinafter is administeredto the patient.

The pharmaceutical composition according to this invention may also havevaluable disease-modifying properties with respect to diseases orconditions related to impaired glucose tolerance (IGT), impaired fastingblood glucose (IFG), insulin resistance and/or metabolic syndrome.

According to another aspect of the invention, there is provided a methodfor preventing, slowing, delaying or reversing progression from impairedglucose tolerance (IGT), impaired fasting blood glucose (IFG), insulinresistance and/or from metabolic syndrome to type 2 diabetes mellitus ina patient in need thereof characterized in that an SGLT2 inhibitor asdefined hereinbefore and hereinafter is administered to the patient.

As by the use of a pharmaceutical composition according to thisinvention, an improvement of the glycemic control in patients in needthereof is obtainable, also those conditions and/or diseases related toor caused by an increased blood glucose level may be treated.

According to another aspect of the invention, there is provided a methodfor preventing, slowing the progression of, delaying or treating of acondition or disorder selected from the group consisting ofcomplications of diabetes mellitus such as cataracts and micro- andmacrovascular diseases, such as nephropathy, retinopathy, neuropathy,tissue ischaemia, diabetic foot, arteriosclerosis, myocardialinfarction, accute coronary syndrome, unstable angina pectoris, stableangina pectoris, stroke, peripheral arterial occlusive disease,cardiomyopathy, heart failure, heart rhythm disorders and vascularrestenosis, in a patient in need thereof characterized in that an SGLT2inhibitor as defined hereinbefore and hereinafter is administered to thepatient. In particular one or more aspects of diabetic nephropathy suchas hyperperfusion, proteinuria and albuminuria may be treated, theirprogression slowed or their onset delayed or prevented. The term “tissueischaemia” particularly comprises diabetic macroangiopathy, diabeticmicroangiopathy, impaired wound healing and diabetic ulcer. The terms“micro- and macrovascular diseases” and “micro- and macrovascularcomplications” are used interchangeably in this application.

By the administration of a pharmaceutical composition according to thisinvention and due to the activity of the SGLT2 inhibitor excessive bloodglucose levels are not converted to insoluble storage forms, like fat,but excreted through the urine of the patient. In animal models it canbe seen that loss of fat accounts for the majority of the observedweight loss whereas no significant changes in body water or proteincontent are observed. Therefore, no gain in weight or even a reductionin body weight is the result.

According to another aspect of the invention, there is provided a methodfor reducing body weight and/or body fat, or preventing an increase inbody weight and/or body fat, or facilitating a reduction in body weightand/or body fat, in a patient in need thereof characterized in that anSGLT2 inhibitor as defined hereinbefore and hereinafter is administeredto the patient.

The pharmacological effect of the SGLT2 inhibitor in the pharmaceuticalcomposition according to this invention is independent of insulin.Therefore, an improvement of the glycemic control is possible without anadditional strain on the pancreatic beta cells. By an administration ofa pharmaceutical composition according to this invention a beta-celldegeneration and a decline of beta-cell functionality such as forexample apoptosis or necrosis of pancreatic beta cells can be delayed orprevented. Furthermore, the functionality of pancreatic cells can beimproved or restored, and the number and size of pancreatic beta cellsincreased. It may be shown that the differentiation status andhyperplasia of pancreatic beta-cells disturbed by hyperglycemia can benormalized by treatment with a pharmaceutical composition according tothis invention.

According to another aspect of the invention, there is provided a methodfor preventing, slowing, delaying or treating the degeneration ofpancreatic beta cells and/or the decline of the functionality ofpancreatic beta cells and/or for improving and/or restoring thefunctionality of pancreatic beta cells and/or restoring thefunctionality of pancreatic insulin secretion in a patient in needthereof characterized in that an SGLT2 inhibitor as defined hereinbeforeand hereinafter is administered to the patient.

By the administration of a pharmaceutical composition according to thepresent invention, an abnormal accumulation of ectopic fat, inparticular of the liver, may be reduced or inhibited. Therefore,according to another aspect of the present invention, there is provideda method for preventing, slowing, delaying or treating diseases orconditions attributed to an abnormal accumulation of ectopic fat, inparticular liver fat, in a patient in need thereof characterized in thatan SGLT2 inhibitor as defined hereinbefore and hereinafter isadministered to the patient. Diseases or conditions which are attributedto an abnormal accumulation of liver fat are particularly selected fromthe group consisting of general fatty liver, non-alcoholic fatty liver(NAFL), non-alcoholic steatohepatitis (NASH), hyperalimentation-inducedfatty liver, diabetic fatty liver, alcoholic-induced fatty liver ortoxic fatty liver.

As a result thereof, another aspect of the invention provides a methodfor maintaining and/or improving the insulin sensitivity and/or fortreating or preventing hyperinsulinemia and/or insulin resistance in apatient in need thereof characterized in that an SGLT2 inhibitor asdefined hereinbefore and hereinafter is administered to the patient.

According to another aspect of the invention, there is provided a methodfor preventing, slowing progression of, delaying, or treating new onsetdiabetes after transplantation (NODAT) and/or post-transplant metabolicsyndrome (PTMS).

According to a further aspect of the invention, there is provided amethod for preventing, delaying, or reducing NODAT and/or PTMSassociated complications including micro- and macrovascular diseases andevents, graft rejection, infection, and death.

The pharmaceutical composition according to the invention is capable offacilitating the lowering of serum total urate levels in the patient.Therefore according to another aspect of the invention, there isprovided a method for treating hyperuricemia andhyperuricemia-associated conditions, such as for example gout,hypertension and renal failure, in a patient in need thereof. Thepatient may be a diabetic or non-diabetic patient.

The administration of a pharmaceutical composition increases the urineexcretion of glucose. This increase in osmotic excretion and waterrelease and the lowering of urate levels are beneficial as a treatmentor prevention for kidney stones. Therefore in a further aspect of theinvention, there is provided a method for treating or preventing kidneystones.

According to a further aspect of the invention, there is provided amethod for treating hyponatremia, water retention and waterintoxication. By the administration of the pharmaceutical compositionaccording to this invention it may be possible to reverse the effects ofhyponatremia, water retention and water intoxication by acting on thekidney to reverse water retention and electrolyte imbalances associatedwith these diseases and disorders.

According to another aspect of the invention there is provided the useof an SGLT2 inhibitor for the manufacture of a medicament for

-   -   preventing, slowing the progression of, delaying or treating a        metabolic disorder selected from the group consisting of type 1        diabetes mellitus, type 2 diabetes mellitus, impaired glucose        tolerance (IGT), impaired fasting blood glucose (IFG),        hyperglycemia, postprandial hyperglycemia, overweight, obesity,        metabolic syndrome and gestational diabetes; or    -   improving glycemic control and/or for reducing of fasting plasma        glucose, of postprandial plasma glucose and/or of glycosylated        hemoglobin HbA1c; or    -   preventing, slowing, delaying or reversing progression from        impaired glucose tolerance (IGT), impaired fasting blood glucose        (IFG), insulin resistance and/or from metabolic syndrome to type        2 diabetes mellitus; or    -   preventing, slowing the progression of, delaying or treating of        a condition or disorder selected from the group consisting of        complications of diabetes mellitus such as cataracts and micro-        and macrovascular diseases, such as nephropathy, retinopathy,        neuropathy, tissue ischaemia, diabetic foot, arteriosclerosis,        myocardial infarction, accute coronary syndrome, unstable angina        pectoris, stable angina pectoris, stroke, peripheral arterial        occlusive disease, cardiomyopathy, heart failure, heart rhythm        disorders and vascular restenosis,; or    -   reducing body weight and/or body fat, or preventing an increase        in body weight and/or body fat, or facilitating a reduction in        body weight and/or body fat; or    -   preventing, slowing, delaying or treating the degeneration of        pancreatic beta cells and/or the decline of the functionality of        pancreatic beta cells and/or for improving and/or restoring the        functionality of pancreatic beta cells and/or restoring the        functionality of pancreatic insulin secretion; or    -   preventing, slowing, delaying or treating diseases or conditions        attributed to an abnormal accumulation of ectopic fat; or    -   maintaining and/or improving the insulin sensitivity and/or for        treating or preventing hyperinsulinemia and/or insulin        resistance;    -   preventing, slowing progression of, delaying, or treating new        onset diabetes after transplantation (NODAT) and/or        post-transplant metabolic syndrome (PTMS);    -   preventing, delaying, or reducing NODAT and/or PTMS associated        complications including micro- and macrovascular diseases and        events, graft rejection, infection, and death;    -   treating hyperuricemia and hyperuricemia associated conditions;    -   treating or prevention kidney stones;    -   treating hyponatremia;        in a patient in need thereof characterized in that the SGLT2        inhibitor is administered, as defined hereinbefore and        hereinafter.

According to another aspect of the invention, there is provided the useof a pharmaceutical composition according to the present invention forthe manufacture of a medicament for a therapeutic and preventive methodas described hereinbefore and hereinafter.

Definitions

The term “active ingredient” of a pharmaceutical composition accordingto the present invention means the SGLT2 inhibitor according to thepresent invention. An “active ingredient is also sometimes referred toherein as an “active substance”.

The term “body mass index” or “BMI” of a human patient is defined as theweight in kilograms divided by the square of the height in meters, suchthat BMI has units of kg/m².

The term “overweight” is defined as the condition wherein the individualhas a BMI greater than or 25 kg/m² and less than 30 kg/m². The terms“overweight” and “pre-obese” are used interchangeably.

The term “obesity” is defined as the condition wherein the individualhas a BMI equal to or greater than 30 kg/m². According to a WHOdefinition the term obesity may be categorized as follows: the term“class I obesity” is the condition wherein the BMI is equal to orgreater than 30 kg/m² but lower than 35 kg/m²; the term “class IIobesity” is the condition wherein the BMI is equal to or greater than 35kg/m² but lower than 40 kg/m²; the term “class III obesity” is thecondition wherein the BMI is equal to or greater than 40 kg/m².

The term “visceral obesity” is defined as the condition wherein awaist-to-hip ratio of greater than or equal to 1.0 in men and 0.8 inwomen is measured. It defines the risk for insulin resistance and thedevelopment of pre-diabetes.

The term “abdominal obesity” is usually defined as the condition whereinthe waist circumference is >40 inches or 102 cm in men, and is >35inches or 94 cm in women. With regard to a Japanese ethnicity orJapanese patients abdominal obesity may be defined as waistcircumference 85 cm in men and 90 cm in women (see e.g. investigatingcommittee for the diagnosis of metabolic syndrome in Japan).

The term “euglycemia” is defined as the condition in which a subject hasa fasting blood glucose concentration within the normal range, greaterthan 70 mg/dL (3.89 mmol/L) and less than 100 mg/dL (5.6 mmol/L). Theword “fasting” has the usual meaning as a medical term.

The term “hyperglycemia” is defined as the condition in which a subjecthas a fasting blood glucose concentration above the normal range,greater than 100 mg/dL (5.6 mmol/L). The word “fasting” has the usualmeaning as a medical term.

The term “hypoglycemia” is defined as the condition in which a subjecthas a blood glucose concentration below the normal range, in particularbelow 70 mg/dL (3.89 mmol/L).

The term “postprandial hyperglycemia” is defined as the condition inwhich a subject has a 2 hour postprandial blood glucose or serum glucoseconcentration greater than 200 mg/dL (11.11 mmol/L).

The term “impaired fasting blood glucose” or “IFG” is defined as thecondition in which a subject has a fasting blood glucose concentrationor fasting serum glucose concentration in a range from 100 to 125 mg/dl(i.e. from 5.6 to 6.9 mmol/l), in particular greater than 110 mg/dL andless than 126 mg/dl (7.00 mmol/L). A subject with “normal fastingglucose” has a fasting glucose concentration smaller than 100 mg/dl,i.e. smaller than 5.6 mmol/l.

The term “impaired glucose tolerance” or “IGT” is defined as thecondition in which a subject has a 2 hour postprandial blood glucose orserum glucose concentration greater than 140 mg/dl (7.78 mmol/L) andless than 200 mg/dL (11.11 mmol/L). The abnormal glucose tolerance, i.e.the 2 hour postprandial blood glucose or serum glucose concentration canbe measured as the blood sugar level in mg of glucose per dL of plasma 2hours after taking 75 g of glucose after a fast. A subject with “normalglucose tolerance” has a 2 hour postprandial blood glucose or serumglucose concentration smaller than 140 mg/dl (7.78 mmol/L).

The term “hyperinsulinemia” is defined as the condition in which asubject with insulin resistance, with or without euglycemia, has fastingor postprandial serum or plasma insulin concentration elevated abovethat of normal, lean individuals without insulin resistance, having awaist-to-hip ratio <1.0 (for men) or <0.8 (for women).

The terms “insulin-sensitizing”, “insulin resistance-improving” or“insulin resistance-lowering” are synonymous and used interchangeably.

The term “insulin resistance” is defined as a state in which circulatinginsulin levels in excess of the normal response to a glucose load arerequired to maintain the euglycemic state (Ford E S, et al. JAMA. (2002)287:356-9). A method of determining insulin resistance is theeuglycaemic-hyperinsulinaemic clamp test. The ratio of insulin toglucose is determined within the scope of a combined insulin-glucoseinfusion technique. There is found to be insulin resistance if theglucose absorption is below the 25th percentile of the backgroundpopulation investigated (WHO definition). Rather less laborious than theclamp test are so called minimal models in which, during an intravenousglucose tolerance test, the insulin and glucose concentrations in theblood are measured at fixed time intervals and from these the insulinresistance is calculated. With this method, it is not possible todistinguish between hepatic and peripheral insulin resistance.

Furthermore, insulin resistance, the response of a patient with insulinresistance to therapy, insulin sensitivity and hyperinsulinemia may bequantified by assessing the “homeostasis model assessment to insulinresistance (HOMA-IR)” score, a reliable indicator of insulin resistance(Katsuki A, et al. Diabetes Care 2001; 24: 362-5). Further reference ismade to methods for the determination of the HOMA-index for insulinsensitivity (Matthews et al., Diabetologia 1985, 28: 412-19), of theratio of intact proinsulin to insulin (Forst et al., Diabetes 2003,52(Suppl.1): A459) and to an euglycemic clamp study. In addition, plasmaadiponectin levels can be monitored as a potential surrogate of insulinsensitivity. The estimate of insulin resistance by the homeostasisassessment model (HOMA)-IR score is calculated with the formula (GalvinP, et al. Diabet Med 1992;9:921-8):

HOMA-IR=[fasting serum insulin (μU/mL)]×[fasting plasmaglucose(mmol/L)/22.5]

As a rule, other parameters are used in everyday clinical practice toassess insulin resistance. Preferably, the patient's triglycerideconcentration is used, for example, as increased triglyceride levelscorrelate significantly with the presence of insulin resistance.

Patients with a predisposition for the development of IGT or IFG or type2 diabetes are those having euglycemia with hyperinsulinemia and are bydefinition, insulin resistant. A typical patient with insulin resistanceis usually overweight or obese. If insulin resistance can be detected,this is a particularly strong indication of the presence ofpre-diabetes. Thus, it may be that in order to maintain glucosehomoeostasis a person needs 2-3 times as much insulin as a healthyperson, without this resulting in any clinical symptoms.

The methods to investigate the function of pancreatic beta-cells aresimilar to the above methods with regard to insulin sensitivity,hyperinsulinemia or insulin resistance: An improvement of beta-cellfunction can be measured for example by determining a HOMA-index forbeta-cell function (Matthews et al., Diabetologia 1985, 28: 412-19), theratio of intact proinsulin to insulin (Forst et al., Diabetes 2003,52(SuppL1): A459), the insulin/C-peptide secretion after an oral glucosetolerance test or a meal tolerance test, or by employing a hyperglycemicclamp study and/or minimal modeling after a frequently sampledintravenous glucose tolerance test (Stumvoll et al., Eur J Clin Invest2001, 31: 380-81).

The term “pre-diabetes” is the condition wherein an individual ispre-disposed to the development of type 2 diabetes. Pre-diabetes extendsthe definition of impaired glucose tolerance to include individuals witha fasting blood glucose within the high normal range 100 mg/dL (J. B.Meigs, et al. Diabetes 2003; 52:1475-1484) and fasting hyperinsulinemia(elevated plasma insulin concentration). The scientific and medicalbasis for identifying pre-diabetes as a serious health threat is laidout in a Position Statement entitled “The Prevention or Delay of Type 2Diabetes” issued jointly by the American Diabetes Association and theNational Institute of Diabetes and Digestive and Kidney Diseases(Diabetes Care 2002; 25:742-749).

Individuals likely to have insulin resistance are those who have two ormore of the following attributes: 1) overweight or obese, 2) high bloodpressure, 3) hyperlipidemia, 4) one or more 1^(st) degree relative witha diagnosis of IGT or IFG or type 2 diabetes. Insulin resistance can beconfirmed in these individuals by calculating the HOMA-IR score. For thepurpose of this invention, insulin resistance is defined as the clinicalcondition in which an individual has a HOMA-IR score >4.0 or a HOMA-IRscore above the upper limit of normal as defined for the laboratoryperforming the glucose and insulin assays.

The term “type 2 diabetes” is defined as the condition in which asubject has a fasting blood glucose or serum glucose concentrationgreater than 125 mg/dL (6.94 mmol/L). The measurement of blood glucosevalues is a standard procedure in routine medical analysis. If a glucosetolerance test is carried out, the blood sugar level of a diabetic willbe in excess of 200 mg of glucose per dL (11.1 mmol/l) of plasma 2 hoursafter 75 g of glucose have been taken on an empty stomach. In a glucosetolerance test 75 g of glucose are administered orally to the patientbeing tested after 10-12 hours of fasting and the blood sugar level isrecorded immediately before taking the glucose and 1 and 2 hours aftertaking it. In a healthy subject, the blood sugar level before taking theglucose will be between 60 and 110 mg per dL of plasma, less than 200 mgper dL 1 hour after taking the glucose and less than 140 mg per dL after2 hours. If after 2 hours the value is between 140 and 200 mg, this isregarded as abnormal glucose tolerance.

The term “late stage type 2 diabetes mellitus” includes patients with asecondary drug failure, indication for insulin therapy and progressionto micro- and macrovascular complications e.g. diabetic nephropathy, orcoronary heart disease (CHD).

The term “HbA1c” refers to the product of a non-enzymatic glycation ofthe haemoglobin B chain. Its determination is well known to one skilledin the art. In monitoring the treatment of diabetes mellitus the HbA1cvalue is of exceptional importance. As its production dependsessentially on the blood sugar level and the life of the erythrocytes,the HbA1c in the sense of a “blood sugar memory” reflects the averageblood sugar levels of the preceding 4-6 weeks. Diabetic patients whoseHbA1c value is consistently well adjusted by intensive diabetestreatment (i.e. <6.5% of the total haemoglobin in the sample), aresignificantly better protected against diabetic microangiopathy. Forexample, metformin on its own achieves an average improvement in theHbA1c value in the diabetic of the order of 1.0-1.5%. This reduction ofthe HbA1C value is not sufficient in all diabetics to achieve thedesired target range of <6.5% and preferably <6% HbA1c.

The term “insufficient glycemic control” or “inadequate glycemiccontrol” in the scope of the present invention means a condition whereinpatients show HbA1c values above 6.5%, in particular above 7.0%, evenmore preferably above 7.5%, especially above 8%.

The “metabolic syndrome”, also called “syndrome X” (when used in thecontext of a metabolic disorder), also called the “dysmetabolicsyndrome” is a syndrome complex with the cardinal feature being insulinresistance (Laaksonen D E, et al. Am J Epidemiol 2002; 156:1070-7).According to the ATP III/NCEP guidelines (Executive Summary of the ThirdReport of the National Cholesterol Education Program (NCEP) Expert Panelon Detection, Evaluation, and Treatment of High Blood Cholesterol inAdults (Adult Treatment Panel III) JAMA: Journal of the American MedicalAssociation (2001) 285:2486-2497), diagnosis of the metabolic syndromeis made when three or more of the following risk factors are present:

-   -   1. Abdominal obesity, defined as waist circumference >40 inches        or 102 cm in men, and >35 inches or 94 cm in women; or with        regard to a Japanese ethnicity or Japanese patients defined as        waist circumference 85 cm in men and ≥90 cm in women;    -   2. Triglycerides: ≥150 mg/dL    -   3. HDL-cholesterol <40 mg/dL in men    -   4. Blood pressure ≥130/85 mm Hg (SBP≥130 or DBP≥85)    -   5. Fasting blood glucose≥100 mg/dL

The NCEP definitions have been validated (Laaksonen D E, et al. Am JEpidemiol. (2002) 156:1070-7). Triglycerides and HDL cholesterol in theblood can also be determined by standard methods in medical analysis andare described for example in Thomas L (Editor): “Labor and Diagnose”,TH-Books Verlagsgesellschaft mbH, Frankfurt/Main, 2000.

According to a commonly used definition, hypertension is diagnosed ifthe systolic blood pressure (SBP) exceeds a value of 140 mm Hg anddiastolic blood pressure (DBP) exceeds a value of 90 mm Hg. If a patientis suffering from manifest diabetes it is currently recommended that thesystolic blood pressure be reduced to a level below 130 mm Hg and thediastolic blood pressure be lowered to below 80 mm Hg.

The definitions of NODAT (new onset diabetes after transplantation) andPTMS (post-transplant metabolic syndrome) follow closely that of theAmerican Diabetes Association diagnostic criteria for type 2 diabetes,and that of the International Diabetes Federation (IDF) and the AmericanHeart Association/National Heart, Lung, and Blood Institute, for themetabolic syndrome. NODAT and/or PTMS are associated with an increasedrisk of micro- and macrovascular disease and events, graft rejection,infection, and death. A number of predictors have been identified aspotential risk factors related to NODAT and/or PTMS including a higherage at transplant, male gender, the pre-transplant body mass index,pre-transplant diabetes, and immunosuppression.

The term “gestational diabetes” (diabetes of pregnancy) denotes a formof the diabetes which develops during pregnancy and usually ceases againimmediately after the birth.

Gestational diabetes is diagnosed by a screening test which is carriedout between the 24th and 28th weeks of pregnancy. It is usually a simpletest in which the blood sugar level is measured one hour after theadministration of 50 g of glucose solution. If this 1 h level is above140 mg/dl, gestational diabetes is suspected. Final confirmation may beobtained by a standard glucose tolerance test, for example with 75 g ofglucose.

The term “hyperuricemia” denotes a condition of high serum total uratelevels. In human blood, uric acid concentrations between 3.6 mg/dL (ca.214 μmol/L) and 8.3 mg/dL (ca. 494 μmol/L) are considered normal by theAmerican Medical Association. High serum total urate levels, orhyperuricemia, are often associated with several maladies. For example,high serum total urate levels can lead to a type of arthritis in thejoints kown as gout. Gout is a condition created by a build up ofmonosodium urate or uric acid crystals on the articular cartilage ofjoints, tendons and surrounding tissues due to elevated concentrationsof total urate levels in the blood stream. The build up of urate or uricacid on these tissues provokes an inflammatory reaction of thesetissues. Saturation levels of uric acid in urine may result in kidneystone formation when the uric acid or urate crystallizes in the kidney.Additionally, high serum total urate levels are often associated withthe so-called metabolic syndrome, including cardiovascular disease andhypertension.

The term “hyponatremia” denotes a condition of a positive balance ofwater with or without a deficit of sodium, which is recognized when theplasma sodium falls below the level of 135 mml/L. Hyponatremia is acondition which can occur in isolation in individuals that over-consumewater; however, more often hyponatremia is a complication of medicationor other underlying medical condition that leas to a diminishedexcretion of water. Hyponatremia may lead to water intoxication, whichoccurs when the normal tonicity of extracellular fluid falls below thesafe limit, due to retention of excess water. Water intoxication is apotentially fatal disturbance in brain function. Typical symptoms ofwater intoxication include nausea, vomiting, headache and malaise.

The term “SGLT2 inhibitor” in the scope of the present invention relatesto compounds, in particular to glucopyranosyl-derivatives, i.e.compounds having a glucopyranosyl-moiety, which show an inhibitoryeffect on the sodium-glucose transporter 2 (SGLT2), in particular thehuman SGLT2. The inhibitory effect on hSGLT2 measured as 1050 isprerably below 1000 nM, even more preferably below 100 nM, mostpreferably below 50 nM. The inhibitory effect on hSGLT2 can bedetermined by methods known in the literature, in particular asdescribed in the application WO 2005/092877 or WO 2007/093610 (pages23/24), which are incorporated herein by reference in its entirety. Theterm “SGLT2 inhibitor” also comprises any pharmaceutically acceptablesalts thereof, hydrates and solvates thereof, including the respectivecrystalline forms.

The terms “treatment” and “treating” comprise therapeutic treatment ofpatients having already developed said condition, in particular inmanifest form. Therapeutic treatment may be symptomatic treatment inorder to relieve the symptoms of the specific indication or causaltreatment in order to reverse or partially reverse the conditions of theindication or to stop or slow down progression of the disease. Thus thecompositions and methods of the present invention may be used forinstance as therapeutic treatment over a period of time as well as forchronic therapy.

The terms “prophylactically treating”, “preventivally treating” and“preventing” are used interchangeably and comprise a treatment ofpatients at risk to develop a condition mentioned hereinbefore, thusreducing said risk.

The term “tablet” comprises tablets without a coating and tablets withone or more coatings. Furthermore the “term” tablet comprises tabletshaving one, two, three or even more layers and press-coated tablets,wherein each of the beforementioned types of tablets may be without orwith one or more coatings. The term “tablet” also comprises mini, melt,chewable, effervescent and orally disintegrating tablets.

The terms “pharmacopoe” and “pharmacopoeias” refer to standardpharmacopoeias such as the “USP 31-NF 26 through Second Supplement”(United States Pharmacopeial Convention) or the “European Pharmacopoeia6.3” (European Directorate for the Quality of Medicines and Health Care,2000-2009).

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows an X-ray powder diffractogram of the crystalline form(I.9X) of the compound (1.9).

FIG. 2 shows the thermoanalysis and determination of the melting pointvia DSC of the crystalline form (I9.X) of the compound (1.9).

FIGS. 3A and 3B show the blood glucose level and blood glucose AUCresults of the administration of a compound of the invention to ZDFrats.

FIG. 4A shows the results of the body weight analysis in theadministration of a compound of the invention to Wistar rats.

FIG. 4B shows the results of the body fat content analysis in theadministration of a compound of the invention to Wistar rats.

DETAILED DESCRIPTION

The aspects according to the present invention, in particular thepharmaceutical compositions, methods and uses, refer to SGLT2 inhibitorsas defined hereinbefore and hereinafter.

Preferably the SGLT2 inhibitor is selected from aglucopyranosyl-substituted benzene derivative of the formula (I)

wherein R¹ denotes Cl, methyl or cyano; R² denotes H, methyl, methoxy orhydroxy and R³ denotes ethyl, cyclopropyl, ethynyl, ethoxy,(R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy; or a prodrugof one of the beforementioned SGLT2 inhibitors.

Compounds of the formula (I) and methods of their synthesis aredescribed for example in the following patent applications: WO2005/092877, WO 2006/117360, WO 2006/117359, WO 2006/120208, WO2006/064033, WO 2007/031548, WO 2007/093610, WO 2008/020011, WO2008/055870.

In the above glucopyranosyl-substituted benzene derivatives of theformula (I) the following definitions of the substituents are preferred.

Preferably R¹ denotes chloro or cyano; in particular chloro.

Preferably R² denotes H.

Preferably R³ denotes ethyl, cyclopropyl, ethynyl,(R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy. Even morepreferably R³ denotes cyclopropyl, ethynyl, (R)-tetrahydrofuran-3-yloxyor (S)-tetrahydrofuran-3-yloxy. Most preferably R³ denotes ethynyl,(R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy.

Preferred glucopyranosyl-substituted benzene derivatives of the formula(I) are selected from the group of compounds (I.1) to (I.11):

Even more preferred glucopyranosyl-substituted benzene derivatives ofthe formula (I) are selected from the compounds (I.6), (I.7), (I.8),(I.9) and (I.11). Even more preferred glucopyranosyl-substituted benzenederivatives of the formula (I) are selected from the compounds (I.8) and(I.9).

According to this invention, it is to be understood that the definitionsof the above listed glucopyranosyl-substituted benzene derivatives ofthe formula (I) also comprise their hydrates, solvates and polymorphicforms thereof, and prodrugs thereof. With regard to the preferredcompound (I.7) an advantageous crystalline form is described in theinternational patent application WO 2007/028814 which hereby isincorporated herein in its entirety. With regard to the preferredcompound (I.8), an advantageous crystalline form is described in theinternational patent application WO 2006/117360 which hereby isincorporated herein in its entirety. With regard to the preferredcompound (I.9) an advantageous crystalline form is described in theinternational patent applciation WO 2006/117359 which hereby isincorporated herein in its entirety. With regard to the preferredcompound (I.11) an advantageous crystalline form is described in theinternational patent applciation WO 2008/049923 which hereby isincorporated herein in its entirety. These crystalline forms possessgood solubility properties which enable a good bioavailability of theSGLT2 inhibitor. Furthermore, the crystalline forms arephysico-chemically stable and thus provide a good shelf-life stabilityof the pharmaceutical composition.

For avoidance of any doubt, the disclosure of each of the foregoingdocuments cited above in connection with the specified SGLT2 inhibitorsis specifically incorporated herein by reference in its entirety.

A preferred crystalline form (I.9X) of the compound (I.9) can becharacterized by an X-ray powder diffraction pattern that comprisespeaks at 18.84, 20.36 and 25.21 degrees 20 (±0.1 degrees 2Θ), whereinsaid X-ray powder diffraction pattern (XRPD) is made using CuK_(α1)radiation.

In particular said X-ray powder diffraction pattern comprises peaks at14.69, 18.84, 19.16, 19.50, 20.36 and 25.21 degrees 2Θ (±0.1 degrees2Θ), wherein said X-ray powder diffraction pattern is made usingCuK_(α1) radiation.

In particular said X-ray powder diffraction pattern comprises peaks at14.69, 17.95, 18.43, 18.84, 19.16, 19.50, 20.36, 22.71, 23.44, 24.81,25.21 and 25.65 degrees 2Θ (±0.1 degrees 2Θ), wherein said X-ray powderdiffraction pattern is made using CuK_(α1) radiation.

More specifically, the crystalline form (I.9X) is characterised by anX-ray powder diffraction pattern, made using CuK_(α1) radiation, whichcomprises peaks at degrees 2Θ (±0.1 degrees 2Θ) as contained in Table 1.

TABLE 1 X-ray powder diffraction pattern of the crystalline form (I.9X)(only peaks up to 30° in 2Θ are listed): 2Θ d-value Intensity I/I₀ [°][Å] [%] 4.46 19.80 8 9.83 8.99 4 11.68 7.57 4 13.35 6.63 14 14.69 6.0342 15.73 5.63 16 16.20 5.47 8 17.95 4.94 30 18.31 4.84 22 18.43 4.81 2318.84 4.71 100 19.16 4.63 42 19.50 4.55 31 20.36 4.36 74 20.55 4.32 1321.18 4.19 11 21.46 4.14 13 22.09 4.02 19 22.22 4.00 4 22.71 3.91 2823.44 3.79 27 23.72 3.75 3 24.09 3.69 3 24.33 3.66 7 24.81 3.59 24 25.213.53 46 25.65 3.47 23 26.40 3.37 2 26.85 3.32 8 27.26 3.27 17 27.89 3.202 28.24 3.16 3 29.01 3.08 4 29.41 3.03 18

Even more specifically, the crystalline form (I.9X) is characterised byan X-ray powder diffraction pattern, made using CuK_(α1) radiation,which comprises peaks at degrees 2Θ (±0.1 degrees 2Θ) as shown in FIG.1.

Furthermore the crystalline form (I.9X) is characterised by a meltingpoint of about 149° C.±3° C. (determined via DSC; evaluated asonset-temperature; heating rate 10 K/min).The obtained DSC curve isshown in FIG. 2.

The X-ray powder diffraction patterns are recorded, within the scope ofthe present invention, using a STOE—STADI P-diffractometer intransmission mode fitted with a location-sensitive detector □(OED) and aCu-anode as X-ray source (CuKα1 radiation, □λ=1,54056 Å, 40 kV, 40 mA).In the Table 1 above the values “2Θ [°]” denote the angle of diffractionin degrees and the values “d [Å]” denote the specified distances in Åbetween the lattice planes. The intensity shown in the FIG. 1 is givenin units of cps (counts per second).

In order to allow for experimental error, the above described 2Θ valuesshould be considered accurate to ±0.1 degrees 2Θ, in particular ±0.05degrees 2Θ. That is to say, when assessing whether a given sample ofcrystals of the compound (I.9) is the crystalline form in accordancewith the invention, a 2Θ value which is experimentally observed for thesample should be considered identical with a characteristic valuedescribed above if it falls within ±0.1 degrees 2Θ of the characteristicvalue, in particular if it falls within ±0.05 degrees 2Θ of thecharacteristic value.

The melting point is determined by DSC (Differential Scanningcalorimetry) using a DSC 821 (Mettler Toledo).

In one embodiment, a pharmaceutical composition or dosage form accordingto the present invention comprises the compound (I.9), wherein at least50% by weight of the compound (I.9) is in the form of its crystallineform (I.9X) as defined hereinbefore. Preferably in said composition ordosage form at least 80% by weight, more preferably at least 90% byweight of the compound (I.9) is in the form of its crystalline form(I.9X) as defined hereinbefore.

Regarding the active pharmaceutical ingredients it can be found that thedissolution properties of the pharmaceutical composition and dosage formis affected inter alia by the particle size and particle sizedistribution of the respective active pharmaceutical ingredient. In thepharmaceutical composition and pharmaceutical dosage form according tothe invention the active pharmaceutical ingredients preferably have aparticle size distribution such that at least 90% of the respectiveactive pharmaceutical ingredient particles, with regard to thedistribution by volume, has a particle size smaller than 200 μm, i.e.X90<200 μm.

In particular, with regard to the glucopyranosyl-substituted benzenederivative of the formula (I), in particular the compound (I.9) or itscrystalline form (I.9X), it was found that the particle size influencethe manufacturability, in particular that too small particles influencethe manufacturability by sticking or filming. On the other hand toolarge particles negatively affect the dissolution properties of thepharmaceutical composition and dosage form and thus the bioavailability.In the following preferred ranges of the particle size distribution aredescribed.

Therefore, in one aspect, in the pharmaceutical composition andpharmaceutical dosage form according to the invention theglucopyranosyl-substituted benzene derivative of the formula (I), inparticular the compound (I.9), preferably its crystalline form (I9.X),preferably has a particle size distribution (by volume) such that atleast 90% of the respective active pharmaceutical ingredient has aparticle size smaller than 200 μm, i.e. X90<200 μm, preferably X90 150μm. More preferably the particle size distribution is such that X90≤100μm, even more preferably X90≤90 μm. In addition the particle sizedistribution is preferably such that X90≥1 μm, more preferably X90≥5 μm,even more preferably X90≥10 μm. Therefore preferred particle sizedistributions are such that 1 μm≤X90≤200 μm, particularly 1 μm≤X90≤150μm, more preferably 5 μm≤X90≤150 μm, even more preferably 5 μm≤X90≤100μm, even more preferably 10 μm≤X90≤100 μm. A preferred example X90≤75μm. Another preferred example is 20 μm≤X90≤50 μm.

Furthermore in the pharmaceutical composition and pharmaceutical dosageform according to the invention the glucopyranosyl-substituted benzenederivative of the formula (I), in particular the compound (I.9),preferably its crystalline form (I9.X), preferably has a particle sizedistribution (by volume) such that X50≤90 μm, more preferably X50≤75 μm,even more preferably X50≤50 μm, most preferably X50≤40 μm. In additionthe particle size distribution is preferably such that X50≥1 μm, morepreferably X50≥5 μm, even more preferably X50≥8 μm. Therefore preferredparticle size distributions are such that 1 μm≤X50≤90 μm, particularly 1μm≤X50≤75 μm, more preferably 5 μm≤X50≤75 μm, even more preferably 5μm≤X50≤50 μm. A preferred example is 8 μm≤X50≤40 μm.

Furthermore in the pharmaceutical composition and pharmaceutical dosageform according to the invention the glucopyranosyl-substituted benzenederivative of the formula (I), in particular the compound (I.9),preferably its crystalline form (I9.X), preferably has a particle sizedistribution (by volume) such that X10≤0.1 μm, more preferably X10≤0.5μm, even more preferably X10≤1 μm, in particular X10≤2 μm.

Therefore a pharmaceutical composition or pharmaceutical dosage formaccording to this invention may preferably be characterized by the abovespecified particle size distributions X90, X50 and/or X10 or one of thefollowing embodiments:

Glucopyranosyl-substituted benzene derivative, in particular ofEmbodiment the compound (I.9) 1 X90 < 200 μm 2 1 μm ≤ X90 ≤ 150 μm 3 5μm ≤ X90 ≤ 150 μm 4 10 μm ≤ X90 ≤ 100 μm 5 X90 ≤150 μm 1 μm ≤ X50 ≤ 75μm 6 X90 ≤ 150 μm 5 μm ≤ X50 ≤ 50 μm 7 X90 ≤ 150 μm 1 μm ≤ X50 ≤ 75 μmX10 ≥0.1 μm 8 X90 ≤150 μm 5 μm ≤ X50 ≤ 50 μm X10 ≥ 0.5 μm

The value X90 refers to the 90% value of the volume distributionmeasured using a laser diffractometer. In other words, for the purposesof the present invention, the X90 value denotes the particle size belowwhich 90% of the quantity of particles is found based on the volumedistribution. Analogously the value X50 refers to the 50% value (median)of the volume distribution measured using a laser diffractometer. Inother words, for the purposes of the present invention, the X50 valuedenotes the particle size below which 50% of the quantity of particlesis found based on the volume distribution. Analogously the value X10refers to the 10% value of the volume distribution measured using alaser diffractometer. In other words, for the purposes of the presentinvention, the X10 value denotes the particle size below which 10% ofthe quantity of particles is found based on the volume distribution.

Preferably all X90, X50, X10 values hereinbefore and hereinafter are byvolume and determined by laser-diffraction method, in particular lowangle laser light scattering, i.e. Fraunhofer diffraction. A preferredtest is described in the experimental section. The laser diffractionmethod is sensitive to the volume of a particle and provides avolume-average particle size, which is equivalent to the weight-averageparticle size if the density is constant. The skilled artesian knowsthat the results of the particle size distribution determination by onetechnique can be correlated with that from another technique, forexample on an empirical basis by routine experimentation. Alternativelythe particle size distribution in the pharmaceutical composition ordosage form can be determined by microscopy, in particular electronmicroscopy or scanning electron microscopy.

In the following the suitable excipients and carriers in thepharmaceutical compositions according to the invention are described infurther detail.

A pharmaceutical composition according to the invention typicallycomprises one or more diluents, one or more disintegrants and optionallyone or more binders. Some of the excipients may have two or morefunctions at the same time, e.g. act as a filler and a binder.

Suitable diluents according to the invention are for example, lactose,in particular lactose monohydrate, cellulose and derivatives, such aspowdered cellulose, microcrystalline or silicified microcrystallinecellulose, cellulose acetate, starches and derivatives such aspregelatinized starch, corn starch, wheat starch, rice starch, potatostarch, sterilizable maize, sodium chloride, calcium carbonate, calciumphosphate, particularly dibasic calcium phosphate, calcium sulphate,dicalcium or tricalcium phosphate, magnesium carbonate, magnesium oxide,sugars and derivatives such as confectioner's sugar, fructose, sucrose,dextrates, dextrin, D-sorbitol sulfobutylether B-cyclodextrin, dextrose,polydextrose, trehalose, maltose, maltitol, mannitol, maltodextrin,sorbitol, inulin, xylitol, erythritol, isomalt, kaolin and lactitol.Preferred diluents are lactose monohydrate and microcrystallinecellulose.

Suitable disintegrants according to the invention are for examplepowdered cellulose, crospovidone, croscarmellose sodium, docusatesodium, low-substituted hydroxypropyl cellulose, magnesium aluminumsilicate, microcrystalline cellulose, polacrilin potassium, sodiumstarch glycolate, starch, particularly pregelatinized starch and cornstarch. A preferred disintegrant is croscarmellose sodium.

Any binder usually employed in pharmaceutical compositions may be usedin the context of the instant invention. Binders are for examplenaturally occurring or partially or totally synthetic polymers selectedfrom acacia, agar, alginic acid, carbomers, carmellose sodium,carrageenan, cellulose acetate phthalate, ceratonia, chitosan,confectionar's sugar, copovidone, povidone, cottonseed oil, dextrate,dextrin, dextrose, polydextrose, maltodextrin, maltose, cellulose andderivatives thereof such as microcrystalline cellulose, methylcellulose,ethylcellulose, hydroxyethyl cellulose, hydroxyethyl methylcellulose,hydroxypropyl celluloses, carboxymethylcelluloses, hypromelloses(cellulose hydroxypropyl methyl ether), starch and derivatives thereof,such as pregelatinized starch, hydroxypropylstarch, corn starch,gelatin, glyceryl behenate, tragacanth, guar gum, hydrogenated vegetableoils, inulin, poloxamer, polycarbophils, polyethylene oxide,polyvinylpyrrolidone, copolymers of N-vinylpyrrolidone and vinylacetate, polymethacrylates, polyethylene glycols, alginates such assodium alginate, gelatin, sucrose, sunflower oil, zein as well asderivatives and mixtures thereof. Preferred binders are microcrystallinecellulose and hydroxypropyl cellulose.

The pharmaceutical composition according to the present invention mayalso comprise one or more lubricants. Suitable lubricants according tothe invention are stearic acid as well as salts thereof including talc,sodium stearate, calcium stearate, zinc stearate, magnesium stearate,sodium stearyl fumarate, glyceryl monostearate, particularly magnesiumstearate, polyethylene glycols, in particular polyethylene glycol with amolecular weight in a range from about 4400 to about 9000, hydrogenatedcastor oil, fatty acid, for example fumaric acid, and salts of fattyacids, in particular the calcium, magnesium, sodium or pottasium saltsthereof, for example calcium behenate, calcium stearate, sodium stearylfumarate or magnesium stearate (for example (e.g. HyQual®,Mallinckrodt), glycerides such as glyceryl behenate (Compritol® 888),Dynasan® 118 or Boeson® VP.

The pharmaceutical composition according to the present invention mayalso comprise one or more glidants. Suitable glidants according to theinvention are silicon dioxide, particularly colloidal silicon dioxide(e.g. Aerosil®, Cab-O-Sil®), stearic acid as well as salts thereofincluding sodium stearate, calcium stearate, zinc stearate, magnesiumstearate, magnesium silicate, calcium silicate, magnesium trisilicateand talc. Preferred glidants are colloidal silicon dioxide and talc.

In another embodiment, a pharmaceutical composition according to theinstant invention comprises

Amount (% by weight) Active ingredient 0.5-25  One or more diluents65-93 One or more binders 1-5 One or more disintegrants 1-4 Optionallyadditional additives ad 100%

In one aspect, the active ingredient is a compound of the formula (I),for example of the formula (I.9) or its crystalline form (I.9X).

In another embodiment, a pharmaceutical composition according to theinstant invention comprises

Amount (% by weight) Active ingredient 0.5-25  One or more diluents65-90 One or more binders 1-5 One or more disintegrants 1-3 Optionallyadditional additives ad 100%

The active ingredient is a compound of the formula (I), for example ofthe formula (I.9) or its crystalline form (I.9X).

In another embodiment, a pharmaceutical composition according to theinstant invention comprises

Amount (% by weight) Active ingredient 0.5-25  Lactose monohydrate 28-70Microcrystalline cellulose 20-50 Hydroxypropyl cellulose 1-5Croscarmellose sodium 1-4 Optionally additional additives ad 100%

In one aspect, the active ingredient is a compound of the formula (I),for example of the formula (I.9) or its crystalline form (I.9X).

In another embodiment, a pharmaceutical composition according to theinstant invention comprises

Amount (% by weight) Active ingredient 0.5-25  Lactose monohydrate 35-90Microcrystalline cellulose  0-30 Hydroxypropyl cellulose 1-5Croscarmellose sodium 1-3 Additional additives ad 100%

The active ingredient is a compound of the formula (I), for example ofthe formula (I.9) or its crystalline form (I.9X).

In one embodiment, the ratio of said disintegrant to said binder in apharmaceutical composition of the present invention is between 1.5:3.5and 1:1.

In one embodiment, the active ingredient represents 25% or less of theweight of the pharmaceutical composition. Preferably, the activeingredient represents 0.5% to 25% of the weight of the pharmaceuticalcomposition. More preferably, the active ingredient represents 1.0% to20% of the weight of the pharmaceutical composition. Even morepreferably, the active ingredient represents 2.0% to 15% of the weightof the pharmaceutical composition.

In the following, preferred ranges of the amount of theglucopyranosyl-substituted benzene derivative to be employed in thepharmaceutical dosage form according to this invention are described.These ranges refer to the amounts to be administered per day withrespect to an adult patient, in particular to a human being, for exampleof approximately 70 kg body weight, and can be adapted accordingly withregard to an administration 2, 3, 4 or more times daily and with regardto other routes of administration and with regard to the age of thepatient. The ranges of the dosage and amounts are calculated for theactive ingredient.

A preferred amount of the glucopyranosyl-substituted benzene derivative,in particular the compound (I.9) or its crystalline form (I.9X) is in arange from 0.5 to 100 mg, preferably from 0.5 to 50 mg, even morepreferably from 1 to 25 mg, even more preferably 5 to 25 mg. Preferreddosages of the glucopyranosyl-substituted benzene derivative are forexample 1 mg, 2 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg,25 mg and 50 mg.

A pharmaceutical composition according to the present invention may becomprised in a tablet, a capsule or a film-coated tablet,

In one embodiment, a tablet comprising a pharmaceutical compositionaccording to the present invention comprises a lubricant, such asmagnesium stearate. Such lubricant may be present in a concentration of0.25-2% in said tablet.

In one embodiment, a tablet comprising a pharmaceutical compositionaccording to the present invention comprises a glidant, such ascolloidal silicon dioxide. Such glidant may be present in aconcentration of 0.25-2% in said tablet.

A tablet according to the invention may be film-coated. Typically a filmcoat represents 2-5% by weight of the total composition and comprisespreferably a film-forming agent, a plasticizer, a glidant and optionallyone or more pigments. An exemplary coat composition may comprisehydroxypropylmethyl-cellulose (HPMC), polyethylene glycol (PEG), talc,titanium dioxide and optionally iron oxide, including iron oxide redand/or yellow.

In one embodiment, the pharmaceutical dosage form according to theinvention has dissolution properties such that after 45 minutes at least75%, preferably at least 90% by weight of the pharmaceutical activeingredient is dissolved. In another embodiment after 30 minutes at least75%, preferably at least 90% by weight of the pharmaceutical activeingredien is dissolved. In another embodiment after 15 minutes at least75%, preferably at least 90% by weight of the pharmaceutical activeingredient is dissolved. The dissolution properties can be determined ina standard dissolution test, for example as described in pharmacopoeias,such as the USP31-NF26 S2, chapter 711 (dissolution).

In one embodiment, the pharmaceutical dosage form according to theinvention has disintegration properties such that within 40 minutes,alternatively within 30 minutes, preferably within 20 minutes, morepreferably within 15 minutes the pharmaceutical dosage form isdisintegrated. The disintegration properties can be determined in astandard disintegration test, for example as described inpharmacopoeias, such as the USP31-NF26 S2, chapter 701 (disintegration).

In one embodiment, the pharmaceutical dosage form according to theinvention has a high content uniformity, preferably within a range from85 to 115%, more preferably from 90 to 110%, even more preferably from95 to 105% by weight with regard to the pharmaceutical ingredient. Thecontent uniformity can be determined in a standard test using forexample randomly 10 selected pharmaceutical dosage forms, for example asdescribed in pharmacopoeias.

A dosage form according to this invention, such as a tablet, capsule orfilm-coated tablet, may be prepared by methods well-known to the oneskilled in the art.

Suitable methods of manufacturing a tablet include compression of thepharmaceutical composition in the form of a powder, i.e. directcompression, or compression of the pharmaceutical composition in theform of granules, and if needed with additional excipients.

Granules of the pharmaceutical composition according to the inventionmay be prepared by methods well-known to the one skilled in the art.Preferred methods for the granulation of the active ingredients togetherwith the excipients include wet granulation, for example high shear wetgranulation and fluidized bed wet granulation, dry granulation, alsocalled roller compaction.

In the wet granulation process the granulation liquid are the solventalone or a preparation of one or more binders in a solvent or mixture ofsolvents. Suitable binders are described hereinbefore. Examples arehypromellose, hydroxypropyl cellulose, povidone and copovidone. Suitablesolvents are for example purified water, ethanol, methanol, isopropanol,acetone, preferably purified water, including mixtures thereof. Thesolvent is a volatile component, which does not remain in the finalproduct. The one or more active ingredients and the other excipients, inparticular the one or more diluents and the one or more disintegrants,usually with exception of the lubricant, are premixed and granulatedwith the granulation liquid, for example using a high shear granulator.The wet granulation step is usually followed by one or more drying andsieving steps. For example a drying oven or a fluid bed dryer can thenbe used for drying.

The dried granules are sieved through an appropriate sieve. Afteroptional addition of the other excipients, in particular disintegrant,binder, filler and/or glidant, with exception of the lubricant themixture is blended in a suitable blender, for example a free fallblender, followed by addition of the one or more lubricants, for examplemagnesium stearate, and final blending in the blender.

An exemplary wet granulation process for making a pharmaceuticalcomposition according to the instant invention comprises the steps of:

-   -   (1) Premixing the active ingredient and the main portion of the        excipients including the binder in a mixer to obtain a        pre-mixture;    -   (2) granulating the pre-mixture of step (1) by adding the        granulation liquid, preferably purified water;    -   (3) drying the granules of step (2) in a fluidized bed dryer or        a drying oven;    -   (4) optionally dry sieving of the dried granules of step (3);    -   (5) mixing the dried granules of step (4) with the remaining        excipients like filler, binder, disintegrant and/or glidant in a        mixer to obtain the main mixture;    -   (6) mixing the main mixture of step (5) with the lubricnat in a        mixer to obtain the final mixture;    -   (7) tableting the final mixture of step (6) by compressing it on        a suitable tablet press to produce tablets cores;    -   (8) optionally film-coating of the tablet cores of step (7) with        a non-functional coat.

The present invention also provides a pharmaceutical compositionobtainable by the above process.

An exemplary direct compression process according to the presentinvention for making a pharmaceutical composition comprises the stepsof:

-   -   (1) Premixing the active ingredient and the main portion of the        excipients in a mixer to obtain a pre-mixture;    -   (2) optionally dry screening the pre-mixture through a screen in        order to segregate cohesive particles and to improve content        uniformity;    -   (3) mixing the pre-mixture of step (1) or (2) in a mixer,        optionally by adding remaining excipients to the mixture and        continuing mixing;    -   (4) tableting the final mixture of step (3) by compressing it on        a suitable tablet press to produce the tablet cores;    -   (5) optionally film-coating of the tablet cores of step (4) with        a non-functional coat.

The present invention also provides a pharmaceutical compositionobtainable by the above process.

An exemplary dry granulation process according to the present inventionfor making a pharmaceutical composition comprises the steps of:

-   -   (1) mixing the active ingredient or a pharmaceutically        acceptable salt thereof with either all or a portion of the        excipients in a mixer;    -   (2) compaction of the mixture of step (1) on a suitable roller        compactor;    -   (3) reducing the ribbons obtained during step (2) to small        granules by suitable milling or sieving steps;    -   (4) optionally mixing the granules of step (3) with the        remaining excipients in a mixer to obtain the final mixture;    -   (5) tabletting the granules of step (3) or the final mixture of        step (4) by compressing it on a suitable tablet press to produce        the tablet cores;    -   (6) optionally film-coating of the tablet cores of step (5) with        a non-functional coat.

In one embodiment, the size of the granules according to the presentinvention is in the range from 25 to 800 μm, for example from 40 μm to500 μm. The size of the granules may be measured via sieve analysis, forexample with a sonic sifter. In one embodiment, at least 80%, at least90%, or at least 95% by weight of the granules is in the given range.

When this invention refers to patients requiring treatment orprevention, it relates primarily to treatment and prevention in humans,but the pharmaceutical composition may also be used accordingly inveterinary medicine in mammals. In the scope of this invention adultpatients are preferably humans of the age of 18 years or older. Also inthe scope of this invention, patients are adolescent humans, i.e. humansof age 10 to 17 years, preferably of age 13 to 17 years. It is assumedthat in a adolescent population the administration of the pharmaceuticalcomposition according to the invention a very good HbA1c lowering and avery good lowering of the fasting plasma glucose can be seen. Inaddition it is assumed that in an adolescent population, in particularin overweight and/or obese patients, a pronounced weight loss can beobserved.

As described hereinbefore by the administration of the pharmaceuticalcomposition according to this invention and in particular in view of thehigh SGLT2 inhibitory activity of the SGLT2 inhibitors therein,excessive blood glucose is excreted through the urine of the patient, sothat no gain in weight or even a reduction in body weight may result.Therefore, a treatment or prophylaxis according to this invention isadvantageously suitable in those patients in need of such treatment orprophylaxis who are diagnosed of one or more of the conditions selectedfrom the group consisting of overweight and obesity, in particular classI obesity, class II obesity, class III obesity, visceral obesity andabdominal obesity. In addition a treatment or prophylaxis according tothis invention is advantageously suitable in those patients in which aweight increase is contraindicated. The pharmaceutical composition aswell as the methods according to the present invention allow a reductionof the HbA1c value to a desired target range, for example <7% andpreferably <6.5%, for a higher number of patients and for a longer timeof therapeutic treatment compared with a corresponding monotherapy or atherapy using only two of the combination partners.

The pharmaceutical composition according to this invention and inparticular the SGLT2 inhibitor therein exhibits a very good efficacywith regard to glycemic control, in particular in view of a reduction offasting plasma glucose, postprandial plasma glucose and/or glycosylatedhemoglobin (HbA1c). By administering a pharmaceutical compositionaccording to this invention, a reduction of HbA1c equal to or greaterthan preferably 0.5%, even more preferably equal to or greater than 1.0%can be achieved and the reduction is particularly in the range from 1.0%to 2.0%.

Furthermore, the method and/or use according to this invention isadvantageously applicable in those patients who show one, two or more ofthe following conditions:

-   -   (a) a fasting blood glucose or serum glucose concentration        greater than 100 mg/dL, in particular greater than 125 mg/dL;    -   (b) a postprandial plasma glucose equal to or greater than 140        mg/dL;    -   (c) an HbA1c value equal to or greater than 6.5%, in particular        equal to or greater than 7.0%, especially equal to or greater        than 7.5%, even more particularly equal to or greater than 8.0%.

The present invention also discloses the use of the pharmaceuticalcomposition for improving glycemic control in patients having type 2diabetes or showing first signs of pre-diabetes. Thus, the inventionalso includes diabetes prevention. If therefore a pharmaceuticalcomposition according to this invention is used to improve the glycemiccontrol as soon as one of the above-mentioned signs of pre-diabetes ispresent, the onset of manifest type 2 diabetes mellitus can be delayedor prevented.

Furthermore, the pharmaceutical composition according to this inventionis particularly suitable in the treatment of patients with insulindependency, i.e. in patients who are treated or otherwise would betreated or need treatment with an insulin or a derivative of insulin ora substitute of insulin or a formulation comprising an insulin or aderivative or substitute thereof. These patients include patients withdiabetes type 2 and patients with diabetes type 1.

Therefore, according to a preferred embodiment of the present invention,there is provided a method for improving glycemic control and/or forreducing of fasting plasma glucose, of postprandial plasma glucoseand/or of glycosylated hemoglobin HbA1c in a patient in need thereof whois diagnosed with impaired glucose tolerance (IGT), impaired fastingblood glucose (IFG) with insulin resistance, with metabolic syndromeand/or with type 2 or type 1 diabetes mellitus characterized in that anSGLT2 inhibitor as defined hereinbefore and hereinafter is administeredto the patient.

According to another preferred embodiment of the present invention,there is provided a method for improving gycemic control in patients, inparticular in adult patients, with type 2 diabetes mellitus as anadjunct to diet and exercise.

It can be found that by using a pharmaceutical composition according tothis invention, an improvement of the glycemic control can be achievedeven in those patients who have insufficient glycemic control inparticular despite treatment with an antidiabetic drug, for exampledespite maximal recommended or tolerated dose of oral monotherapy withmetformin. A maximal recommended dose with regard to metformin is forexample 2000 mg per day or 850 mg three times a day or any equivalentthereof.

Therefore, the method and/or use according to this invention isadvantageously applicable in those patients who show one, two or more ofthe following conditions:

(a) insufficient glycemic control with diet and exercise alone;

(b) insufficient glycemic control despite oral monotherapy withmetformin, in particular despite oral monotherapy at a maximal tolerateddose of metformin;

(c) insufficient glycemic control despite oral monotherapy with anotherantidiabetic agent, in particular despite oral monotherapy at a maximaltolerated dose of the other antidiabetic agent.

The lowering of the blood glucose level by the administration of anSGLT2 inhibitor according to this invention is insulin-independent.Therefore, a pharmaceutical composition according to this invention isparticularly suitable in the treatment of patients who are diagnosedhaving one or more of the following conditions

-   -   insulin resistance,    -   hyperinsulinemia,    -   pre-diabetes,    -   type 2 diabetes mellitus, particular having a late stage type 2        diabetes mellitus,    -   type 1 diabetes mellitus.

Furthermore, a pharmaceutical composition according to this invention isparticularly suitable in the treatment of patients who are diagnosedhaving one or more of the following conditions

(a) obesity (including class I, II and/or III obesity), visceral obesityand/or abdominal obesity,

(b) triglyceride blood level ≥150 mg/dL,

(c) HDL-cholesterol blood level <40 mg/dL in female patients and <50mg/dL in male patients,

(d) a systolic blood pressure ≥130 mm Hg and a diastolic blood pressure≥85 mm Hg,

(e) a fasting blood glucose level ≥100 mg/dL.

It is assumed that patients diagnosed with impaired glucose tolerance(IGT), impaired fasting blood glucose (IFG), with insulin resistanceand/or with metabolic syndrome suffer from an increased risk ofdeveloping a cardiovascular disease, such as for example myocardialinfarction, coronary heart disease, heart insufficiency, thromboembolicevents. A glycemic control according to this invention may result in areduction of the cardiovascular risks.

Furthermore, a pharmaceutical composition according to this invention isparticularly suitable in the treatment of patients after organtransplantation, in particular those patients who are diagnosed havingone or more of the following conditions

(a) a higher age, in particular above 50 years,

(b) male gender;

(c) overweight, obesity (including class I, II and/or III obesity),visceral obesity and/or abdominal obesity,

(d) pre-transplant diabetes,

(e) immunosuppression therapy.

Furthermore, a pharmaceutical composition according to this invention isparticularly suitable in the treatment of patients who are diagnosedhaving one or more of the following conditions:

(a) hyponatremia, in particular chronical hyponatremia;

(b) water intoxication;

(c) water retention;

(d) plasma sodium concentration below 135 mmol/L.

The patient may be a diabetic or non-diabetic mammal, in particularhuman.

Furthermore, a pharmaceutical composition according to this invention isparticularly suitable in the treatment of patients who are diagnosedhaving one or more of the following conditions:

(a) high serum uric acid levels, in particular greater than 6.0 mg/dL(357 μmol/L);

(b) a history of gouty arthritis, in particular recurrent goutyarthritis;

(c) kidney stones, in particular recurrent kidney stones;

(d) a high propensity for kidney stone formation.

A pharmaceutical composition according to this invention exhibits a goodsafety profile. Therefore, a treatment or prophylaxis according to thisinvention is advantageously possible in those patients for which themono-therapy with another antidiabetic drug, such as for examplemetformin, is contraindicated and/or who have an intolerance againstsuch drugs at therapeutic doses. In particular, a treatment orprophylaxis according to this invention may be advantageously possiblein those patients showing or having an increased risk for one or more ofthe following disorders: renal insufficiency or diseases, cardiacdiseases, cardiac failure, hepatic diseases, pulmonal diseases,catabolytic states and/or danger of lactate acidosis, or female patientsbeing pregnant or during lactation.

Furthermore, it can be found that the administration of a pharmaceuticalcomposition according to this invention results in no risk or in a lowrisk of hypoglycemia. Therefore, a treatment or prophylaxis according tothis invention is also advantageously possible in those patients showingor having an increased risk for hypoglycemia.

A pharmaceutical composition according to this invention is particularlysuitable in the long term treatment or prophylaxis of the diseasesand/or conditions as described hereinbefore and hereinafter, inparticular in the long term glycemic control in patients with type 2diabetes mellitus.

The term “long term” as used hereinbefore and hereinafter indicates atreatment of or administration in a patient within a period of timelonger than 12 weeks, preferably longer than 25 weeks, even morepreferably longer than 1 year.

Therefore, a particularly preferred embodiment of the present inventionprovides a method for therapy, preferably oral therapy, for improvement,especially long term improvement, of glycemic control in patients withtype 2 diabetes mellitus, especially in patients with late stage type 2diabetes mellitus, in particular in patients additionally diagnosed ofoverweight, obesity (including class I, class II and/or class IIIobesity), visceral obesity and/or abdominal obesity.

It will be appreciated that the amount of the pharmaceutical compositionaccording to this invention to be administered to the patient andrequired for use in treatment or prophylaxis according to the presentinvention will vary with the route of administration, the nature andseverity of the condition for which treatment or prophylaxis isrequired, the age, weight and condition of the patient, concomitantmedication and will be ultimately at the discretion of the attendantphysician. In general, however, the SGLT2 inhibitor according to thisinvention is included in the pharmaceutical composition or dosage formin an amount sufficient that by its administration the glycemic controlin the patient to be treated is improved.

For the treatment of hyperuricemia or hyperuricemia associatedconditions the SGLT2 inhibitor according to this invention is includedin the pharmaceutical composition or dosage form in an amount sufficientthat is sufficient to treat hyperuricemia without disturbing thepatient's plasma glucose homeostasis, in particular without inducinghypoglycemia.

For the treatment or prevention of kidney stones the SGLT2 inhibitoraccording to this invention is included in the pharmaceuticalcomposition or dosage form in an amount sufficient that is sufficient totreat or prevent kidney stones without disturbing the patient's plasmaglucose homeostasis, in particular without inducing hypoglycemia.

For the treatment of hyponatremia and associated conditions the SGLT2inhibitor according to this invention is included in the pharmaceuticalcomposition or dosage form in an amount sufficient that is sufficient totreat hyponatremia or the associated conditions without disturbing thepatient's plasma glucose homeostasis, in particular without inducinghypoglycemia.

In the following preferred ranges of the amount of the SGLT2 inhibitorto be employed in the pharmaceutical composition and the methods anduses according to this invention are described. These ranges refer tothe amounts to be administered per day with respect to an adult patient,in particular to a human being, for example of approximately 70 kg bodyweight, and can be adapted accordingly with regard to an administration2, 3, 4 or more times daily and with regard to other routes ofadministration and with regard to the age of the patient.

Within the scope of the present invention, the pharmaceuticalcomposition is preferably administered orally. Other forms ofadministration are possible and described hereinafter. Preferably theone or more dosage forms comprising the SGLT2 inhibitor is oral orusually well known.

In general, the amount of the SGLT2 inhibitor in the pharmaceuticalcomposition and methods according to this invention is preferably theamount usually recommended for a monotherapy using said SGLT2 inhibitor.

The preferred dosage range of the SGLT2 inhibitor is in the range from0.5 mg to 200 mg, even more preferably from 1 to 100 mg, most preferablyfrom 1 to 50 mg per day. The oral administration is preferred.Therefore, a pharmaceutical composition may comprise the hereinbeforementioned amounts, in particular from 1 to 50 mg or 1 to 25 mg.Particular dosage strengths (e.g. per tablet or capsule) are for example1, 2.5, 5, 7.5, 10, 12.5, 15, 20, 25 or 50 mg of the SGLT2 inhibitor,such as a compound of the formula (I), in particular of the compound(1.9) or its crystalline form (I.9X). The application of the activeingredient may occur up to three times a day, preferably one or twotimes a day, most preferably once a day.

A pharmaceutical composition which is present as a separate or multipledosage form, preferably as a kit of parts, is useful in combinationtherapy to flexibly suit the individual therapeutic needs of thepatient.

According to a first embodiment a preferred kit of parts comprises acontainment containing a dosage form comprising the SGLT2 inhibitor andat least one pharmaceutically acceptable carrier.

A further aspect of the present invention is a manufacture comprisingthe pharmaceutical composition being present as separate dosage formsaccording to the present invention and a label or package insertcomprising instructions that the separate dosage forms are to beadministered in combination or alternation.

According to a first embodiment a manufacture comprises (a) apharmaceutical composition comprising a SGLT2 inhibitor according to thepresent invention and (b) a label or package insert which comprisesinstructions that the medicament is to be administered.

The desired dose of the pharmaceutical composition according to thisinvention may conveniently be presented in a once daily or as divideddose administered at appropriate intervals, for example as two, three ormore doses per day.

The pharmaceutical composition may be formulated for oral, rectal,nasal, topical (including buccal and sublingual), transdermal, vaginalor parenteral (including intramuscular, sub-cutaneous and intravenous)administration in liquid or solid form or in a form suitable foradministration by inhalation or insufflation. Oral administration ispreferred. The formulations may, where appropriate, be convenientlypresented in discrete dosage units and may be prepared by any of themethods well known in the art of pharmacy. All methods include the stepof bringing into association the active ingredient with one or morepharmaceutically acceptable carriers, like liquid carriers or finelydivided solid carriers or both, and then, if necessary, shaping theproduct into the desired formulation.

The pharmaceutical composition may be formulated in the form of tablets,granules, fine granules, powders, capsules, caplets, soft capsules,pills, oral solutions, syrups, dry syrups, chewable tablets, troches,effervescent tablets, drops, suspension, fast dissolving tablets, oralfast-dispersing tablets, etc..

The pharmaceutical composition and the dosage forms preferably comprisesone or more pharmaceutical acceptable carriers which must be“acceptable” in the sense of being compatible with the other ingredientsof the formulation and not deleterious to the recipient thereof.Examples of pharmaceutically acceptable carriers are known to the oneskilled in the art.

Pharmaceutical compositions suitable for oral administration mayconveniently be presented as discrete units such as capsules, includingsoft gelatin capsules, cachets or tablets each containing apredetermined amount of the active ingredient; as a powder or granules;as a solution, a suspension or as an emulsion, for example as syrups,elixirs or self-emulsifying delivery systems (SEDDS). The activeingredients may also be presented as a bolus, electuary or paste.Tablets and capsules for oral administration may contain conventionalexcipients such as binding agents, fillers, lubricants, disintegrants,or wetting agents. The tablets may be coated according to methods wellknown in the art. Oral liquid preparations may be in the form of, forexample, aqueous or oily suspensions, solutions, emulsions, syrups orelixirs, or may be presented as a dry product for constitution withwater or other suitable vehicle before use. Such liquid preparations maycontain conventional additives such as suspending agents, emulsifyingagents, non-aqueous vehicles (which may include edible oils), orpreservatives.

The pharmaceutical composition according to the invention may also beformulated for parenteral administration (e.g. by injection, for examplebolus injection or continuous infusion) and may be presented in unitdose form in ampoules, pre-filled syringes, small volume infusion or inmulti-dose containers with an added preservative. The compositions maytake such forms as suspensions, solutions, or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilizing and/or dispersing agents. Alternatively, the activeingredients may be in powder form, obtained by aseptic isolation ofsterile solid or by lyophilisation from solution, for constitution witha suitable vehicle, e.g. sterile, pyrogen-free water, before use.

Pharmaceutical compositions suitable for rectal administration whereinthe carrier is a solid are most preferably presented as unit dosesuppositories. Suitable carriers include cocoa butter and othermaterials commonly used in the art, and the suppositories may beconveniently formed by admixture of the active compound(s) with thesoftened or melted carrier(s) followed by chilling and shaping inmoulds.

The pharmaceutical compositions and methods according to this inventionshow advantageous effects in the treatment and prevention of thosediseases and conditions as described hereinbefore. Advantageous effectsmay be seen for example with respect to efficacy, dosage strength,dosage frequency, pharmacodynamic properties, pharmacokineticproperties, fewer adverse effects, convenience, compliance, etc..

Methods for the manufacture of SGLT2 inhibitors according to thisinvention and of prodrugs thereof are known to the one skilled in theart. Advantageously, the compounds according to this invention can beprepared using synthetic methods as described in the literature,including patent applications as cited hereinbefore. Preferred methodsof manufacture are described in the WO 2006/120208 and WO 2007/031548.With regard to compound (I.9) an advantageous crystalline form isdescribed in the international patent application WO 2006/117359 whichhereby is incorporated herein in its entirety.

The active ingredients may be present in the form of a pharmaceuticallyacceptable salt. Pharmaceutically acceptable salts include, withoutbeing restricted thereto, such as salts of inorganic acid likehydrochloric acid, sulfuric acid and phosphoric acid; salts of organiccarboxylic acid like oxalic acid, acetic acid, citric acid, malic acid,benzoic acid, maleic acid, fumaric acid, tartaric acid, succinic acidand glutamic acid and salts of organic sulfonic acid likemethanesulfonic acid and p-toluenesulfonic acid. The salts can be formedby combining the compound and an acid in the appropriate amount andratio in a solvent and decomposer. They can be also obtained by thecation or anion exchange from the form of other salts.

The active ingredients or a pharmaceutically acceptable salt thereof maybe present in the form of a solvate such as a hydrate or alcohol adduct.

Any of the above mentioned pharmaceutical compositions and methodswithin the scope of the invention may be tested by animal models knownin the art. In the following, in vivo experiments are described whichare suitable to evaluate pharmacologically relevant properties ofpharmaceutical compositions and methods according to this invention.

Pharmaceutical compositions and methods according to this invention canbe tested in genetically hyperinsulinemic or diabetic animals like db/dbmice, ob/ob mice, Zucker Fatty (fa/fa) rats or Zucker Diabetic Fatty(ZDF) rats. In addition, they can be tested in animals withexperimentally induced diabetes like HanWistar or Sprague Dawley ratspretreated with streptozotocin.

The effect on glycemic control according to this invention can be testedafter single dosing of the SGLT2 inhibitor in an oral glucose tolerancetest in the animal models described hereinbefore. The time course ofblood glucose is followed after an oral glucose challenge in overnightfasted animals. The pharmaceutical compositions according to the presentinvention significantly improve glucose excursion, for example comparedto another monotherapy, as measured by reduction of peak glucoseconcentrations or reduction of glucose AUC. In addition, after multipledosing of the SGLT2 inhibitor in the animal models describedhereinbefore, the effect on glycemic control can be determined bymeasuring the HbA1c value in blood. The pharmaceutical compositionsaccording to this invention significantly reduce HbA1c, for examplecompared to another monotherapy or compared to a dual-combinationtherapy.

The improved independence from insulin of the treatment according tothis invention can be shown after single dosing in oral glucosetolerance tests in the animal models described hereinbefore. The timecourse of plasma insulin is followed after a glucose challenge inovernight fasted animals.

The increase in active GLP-1 levels by treatment according to thisinvention after single or multiple dosing can be determined by measuringthose levels in the plasma of animal models described hereinbefore ineither the fasting or postprandial state. Likewise, a reduction inglucagon levels in plasma can be measured under the same conditions.

The effect of a SGLT2 inhibitor according to the present invention onbeta-cell regeneration and neogenesis can be determined after multipledosing in the animal models described hereinbefore by measuring theincrease in pancreatic insulin content, or by measuring increasedbeta-cell mass by morphometric analysis after immunhistochemicalstaining of pancreatic sections, or by measuring increasedglucose-stimulated insulin secretion in isolated pancreatic islets.

PHARMACOLOGICAL EXAMPLES

The following examples show the beneficial effect on glycemic control ofthe pharmaceutical compositions according to the present invention.

Example 1

According to a first example an oral glucose tolerance test is performedin overnight fasted 9-weeks old male Zucker Diabetic Fatty (ZDF) rats(ZDF/Crl-Lepr^(fa)). A pre-dose blood sample is obtained by tail bleed.Blood glucose is measured with a glucometer, and the animals arerandomized for blood glucose (n=5/group). Subsequently, the groupsreceive a single oral administration of either vehicle alone (0.5%aqueous hydroxyethylcellulose containing 3 mM HCl and 0.015% Polysorbat80) or vehicle containing the SGLT2 inhibitor. The animals receive anoral glucose load (2 g/kg) 30 min after compound administration. Bloodglucose is measured in tail blood 30 min, 60 min, 90 min, 120 min, and180 min after the glucose challenge. Glucose excursion is quantified bycalculating the reactive glucose AUC. The data are presented asmean±SEM. The two-sided unpaired Student t-test is used for statisticalcomparison of the control group and the active groups.

A representative experiment is shown in FIGS. 3A and 3B. Compound (1.9)(1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene)was orally administered to ZDF rats at doses of 0.3 mg/kg, 3 mg/kg or 30mg/kg body weight. The animals then received an oral glucose bolus andthe resulting glucose-time profile is shown in FIG. 3A. Thebaseline-corrected area under the glucose-time curves are shown in FIG.3B. Compound (1.9) reduced glucose excursion by 15% at 0.3 mg/kg (notsignificant), by 62% at 3 mg/kg (p<0.001) and by 89% at 30 mg/kg(p<0.001).

Example 2

According to a second example an oral glucose tolerance test isperformed in overnight fasted male Sprague Dawley rats (Crl:CD(SD)) witha body weight of about 200 g. A pre-dose blood sample is obtained bytail bleed. Blood glucose is measured with a glucometer, and the animalsare randomized for blood glucose (n=5/group). Subsequently, the groupsreceive a single oral administration of either vehicle alone (0.5%aqueous hydroxyethylcellulose containing 0.015% Polysorbat 80) orvehicle containing the SGLT2 inhibitor. The animals receive an oralglucose load (2 g/kg) 30 min after compound administration. Bloodglucose is measured in tail blood 30 min, 60 min, 90 min, and 120 minafter the glucose challenge. Glucose excursion is quantified bycalculating the reactive glucose AUC. The data are presented asmean±S.E.M. Statistical comparisons are conducted by Student's t test.

Example 3 Treatment of Pre-Diabetes

The efficacy of a pharmaceutical composition according to the inventionin the treatment of pre-diabetes characterised by pathological fastingglucose and/or impaired glucose tolerance can be tested using clinicalstudies. In studies over a shorter period (e.g. 2-4 weeks) the successof the treatment is examined by determining the fasting glucose valuesand/or the glucose values after a meal or after a loading test (oralglucose tolerance test or food tolerance test after a defined meal)after the end of the period of therapy for the study and comparing themwith the values before the start of the study and/or with those of aplacebo group. In addition, the fructosamine value can be determinedbefore and after therapy and compared with the initial value and/or theplacebo value. A significant drop in the fasting or non-fasting glucoselevels demonstrates the efficacy of the treatment. In studies over alonger period (12 weeks or more) the success of the treatment is testedby determining the HbA1c value, by comparison with the initial valueand/or with the value of the placebo group. A significant change in theHbA1c value compared with the initial value and/or the placebo valuedemonstrates the efficacy of the pharmaceutical composition according tothe invention for treating pre-diabetes.

Example 4 Preventing Manifest Type 2 Diabetes

Treating patients with pathological fasting glucose and/or impairedglucose tolerance (pre-diabetes) is also in pursuit of the goal ofpreventing the transition to manifest type 2 diabetes. The efficacy of atreatment can be investigated in a comparative clinical study in whichpre-diabetes patients are treated over a lengthy period (e.g. 1-5 years)with either a pharmaceutical composition according to this invention orwith placebo or with a non-drug therapy or other medicaments. During andat the end of the therapy, by determining the fasting glucose and/or aloading test (e.g. oGTT), a check is made to determine how many patientsexhibit manifest type 2 diabetes, i.e. a fasting glucose level of >125mg/dl and/or a 2h value according to oGTT of >199 mg/dl. A significantreduction in the number of patients who exhibit manifest type 2 diabeteswhen treated with a pharmaceutical composition according to thisinvention as compared to one of the other forms of treatment,demonstrates the efficacy in preventing a transition from pre-diabetesto manifest diabetes.

Example 5 Treatment of Type 2 Diabetes

Treating patients with type 2 diabetes with the pharmaceuticalcomposition according to the invention, in addition to producing anacute improvement in the glucose metabolic situation, prevents adeterioration in the metabolic situation in the long term. This can beobserved is patients are treated for a longer period, e.g. 3 months to 1year or even 1 to 6 years, with the pharmaceutical composition accordingto the invention and are compared with patients who have been treatedwith other antidiabetic medicaments. There is evidence of therapeuticsuccess compared with patients treated with other antidiabeticmedicaments if no or only a slight increase in the fasting glucoseand/or HbA1c value is observed. Further evidence of therapeutic successis obtained if a significantly smaller percentage of the patientstreated with a pharmaceutical composition according to the invention,compared with patients who have been treated with other medicaments,undergo a deterioration in the glucose metabolic position (e.g. anincrease in the HbA1c value to >6.5% or >7%) to the point wheretreatment with an additional oral antidiabetic medicament or withinsulin or with an insulin analogue is indicated.

Example 6 Treatment of Insulin Resistance

In clinical studies running for different lengths of time (e.g. 2 weeksto 12 months) the success of the treatment is checked using ahyperinsulinaemic euglycaemic glucose clamp study. A significant rise inthe glucose infusion rate at the end of the study, compared with theinitial value or compared with a placebo group, or a group given adifferent therapy, proves the efficacy of a pharmaceutical compositionaccording to the invention in the treatment of insulin resistance.

Example 7 Treatment of Hyperglycaemia

In clinical studies running for different lengths of time (e.g. 1 day to24 months) the success of the treatment in patients with hyperglycaemiais checked by determining the fasting glucose or non-fasting glucose(e.g. after a meal or a loading test with oGTT or a defined meal). Asignificant fall in these glucose values during or at the end of thestudy, compared with the initial value or compared with a placebo group,or a group given a different therapy, proves the efficacy of apharmaceutical composition according to the invention in the treatmentof hyperglycaemia.

Example 8 Prevention of Micro- or Macrovascular Complications

The treatment of type 2 diabetes or pre-diabetes patients with apharmaceutical composition according to the invention prevents orreduces or reduces the risk of developing microvascular complications(e.g. diabetic neuropathy, diabetic retinopathy, diabetic nephropathy,diabetic foot, diabetic ulcer) or macrovascular complications (e.g.myocardial infarct, acute coronary syndrome, unstable angina pectoris,stable angina pectoris, stroke, peripheral arterial occlusive disease,cardiomyopathy, heart failure, heart rhythm disorders, vascularrestenosis). Type 2 diabetes or patients with pre-diabetes are treatedlong-term, e.g. for 1-6 years, with a pharmaceutical compositionaccording to the invention and compared with patients who have beentreated with other antidiabetic medicaments or with placebo. Evidence ofthe therapeutic success compared with patients who have been treatedwith other antidiabetic medicaments or with placebo can be found in thesmaller number of single or multiple complications. In the case ofmacrovascular events, diabetic foot and/or diabetic ulcer, the numbersare counted by anamnesis and various test methods. In the case ofdiabetic retinopathy the success of the treatment is determined bycomputer-controlled illumination and evaluation of the background to theeye or other ophthalmic methods. In the case of diabetic neuropathy, inaddition to anamnesis and clinical examination, the nerve conductionrate can be measured using a calibrated tuning fork, for example. Withregard to diabetic nephropathy the following parameters may beinvestigated before the start, during and at the end of the study:secretion of albumin, creatinin clearance, serum creatinin values, timetaken for the serum creatinin values to double, time taken untildialysis becomes necessary.

Example 9 Treatment of Metabolic Syndrome

The efficacy of a pharmaceutical composition according to the inventioncan be tested in clinical studies with varying run times (e.g. 12 weeksto 6 years) by determining the fasting glucose or non-fasting glucose(e.g. after a meal or a loading test with oGTT or a defined meal) or theHbA1c value. A significant fall in these glucose values or HbA1c valuesduring or at the end of the study, compared with the initial value orcompared with a placebo group, or a group given a different therapy,proves the efficacy of an active substance in the treatment of MetabolicSyndrome. Examples of this are a reduction in systolic and/or diastolicblood pressure, a lowering of the plasma triglycerides, a reduction intotal or LDL cholesterol, an increase in HDL cholesterol or a reductionin weight, either compared with the starting value at the beginning ofthe study or in comparison with a group of patients treated with placeboor a different therapy.

Example 10a Prevention of NODAT and/or PTMS, and NODAT/PTMS AssociatedComplications

Treatment of patients after organ transplantation with thepharmaceutical composition according to the invention prevents thedevelopment of NODAT and/or PTMS, and associated complications. Theefficacy of the treatment can be investigated in a comparative clinicalstudy in which patients before or immediately after transplantation aretreated over a lengthy period (e.g. 1-5 years) with either apharmaceutical composition according to this intervention or with aplacebo or with a non-drug therapy or other medicaments. During and atthe end of the therapy, the incidence of NODAT, PTMS, micro- andmacrovascular complications, graft rejection, infection and death willbe assessed. A significant reduction in the number of patientsexperiencing these complications demonstrates the efficacy in preventingdevelopment of NODAT, PTMS, and associated complications.

Example 10b Treatment of NODAT and/or PTMS with Prevention, Delay orReduction of Associated Complications

Treatment of patients with NODAT and/or PTMS with the pharmaceuticalcomposition according to the invention prevents, delays or reduces thedevelopment of NODAT/PTMS associated complications. The efficacy of thetreatment can be investigated in a comparative clinical study in whichpatients with NODAT and/or PTMS are treated over a lengthy period (e.g.1-5 years) with either a pharmaceutical composition according to thisintervention or with a placebo or with a non-drug therapy or othermedicaments. During and at the end of the therapy, the incidence ofmicro- and macrovascular complications, graft rejection, infection anddeath will be assessed. A significant reduction in the number ofpatients experiencing these complications demonstrates the efficacy inpreventing, delaying or reducing the development of NODAT and/or PTMSassociated complications.

Example 11a Treatment of Gestational Diabetes

In clinical studies running for a shorter period (e.g. 2-4 weeks) thesuccess of the treatment is checked by determining the fasting glucosevalues and/or the glucose values after a meal or after a loading test(oral glucose tolerance test or food tolerance test after a definedmeal) at the end of the therapeutic period of the study and comparingthem with the values before the start of the study and/or with those ofa placebo group. In addition, the fructosamine value can be determinedbefore and after treatment and compared with the initial value and/or aplacebo value. A significant fall in the fasting or non-fasting glucoselevels demonstrates the pharmaceutical compositon according to theinvention.

In longer-running studies (12 weeks or more) the success of thetreatment is checked by determining the HbA1c value (compared withinitial value and placebo group). A significant change in the HbA1cvalue compared with the starting value and/or placebo value demonstratesthe efficacy of the pharmaceutical composition according to theinvention in the treatment of gestational diabetes.

Example 11b Treatment of Women who have had Gestational Diabetes

Patients with gestational diabetes have a significantly increased riskof contracting manifest type 2 diabetes after the pregnancy. Therapy maybe provided with the objective of preventing the transition to manifesttype 2. For this purpose, women with a history of gestational diabetesare treated either with a pharmaceutical composition according to theinvention or with placebo or with a non-drug therapy or with othermedicaments, over a lengthy period (e.g. 1-4 years). During and at theend of the treatment a check is carried out by determining the fastingglucose and/or by a loading test (e.g. oGTT) to see how many patientshave developed manifest type 2 diabetes (fasting glucose level>125 mg/dland/or 2 h value after oGTT>199 mg/dl). A significant reduction in thenumber of patients who develop manifest type 2 diabetes when treatedwith a pharmaceutical composition according to the invention comparedwith a different type of therapy, is proof of the efficacy of apharmaceutical composition in preventing manifest diabetes in women witha history of gestational diabetes.

Example 12 Treatment of Hyperuricemia

Patients with elevated levels of uric acid above the normal range (above8.3 mg/dL or 494 pmol/L) or patients with a history of gout or goutyarthritis with a uric acid level greater than 6.0 mg/dL or 357 μmol/Lhave a significant risk of future episodes of gout or gouty arthritis aswell as having an increased risk of cardiovascular disease. Therapy maybe provided with the objective of lowering serum levels of uric acid asa means of preventing future episodes or flare-ups of gout or goutyarthritis. Additionally, lowering serum uric acid levels may reduce therisk of cardiovascular disease. For this purpose patients with anelevated uric acid level or a history of gout or gouty arthritis aretreated either with a pharmaceutical composition according to theinvention or with placebo or with a non-drug therapy or with othermedicaments, over a lengthy period (e.g. 6 months to 4 years). Duringand at the end of the treatment a check is carried out by determiningthe serum uric acid level and the number of episodes of gout or goutyarthritis occurences. A reduction in uric acid below 6.0 mg/dL and/orfewer episodes of gout or gouty arthritis occurrence when treated with apharmaceutical composition according to the invention compared with adifferent type of therapy, is proof of the efficacy of a pharmaceuticalcomposition in preventing episodic gout or gouty arthritis or treatinghyperuricemia.

In a twelve week study of patients with manifest type 2 diabetesmellitus serum uric acid levels were measured at baseline and every 4weeks in patients randomized to an administration of the compound (1.9)of 5 mg, 10 mg, or 25 mg or placebo or metformin 2000 mg, daily for 12weeks. When compared to baseline, patients receiving all doses of thecompound (1.9) had a reduction in their serum uric acid levels of 0.5 to0.7 mg/dL when compared to baseline, while serum uric acid levelsincreased in patients randomized to either metformin or placebo.

Cpd. (I.9) Cpd. (I.9) Cpd. (I.9) Metformin 5 mg 10 mg 25 mg 2000 mgplacebo baseline 5.5 mg/dL 5.3 mg/dL 5.4 mg/dL 5.6 mg/dL 5.4 mg/dL 12weeks 5.0 mg/dL 4.7 mg/dL 4.7 mg/dL 6.2 mg/dL 5.6 mg/dL

Example 13 Treatment of Hyponatremia

Patients with hyponatremia and water intoxication whether due to anincrease in water resorption or an increase in water intake, are at riskof central nervous system abnormalities and possibly death. Therapy maybe provided with the objective of increasing the amount of free water tobe excreted in the renal filtrate without disturbing sodium balance withthe objective of increasing the overall sodium concentration of theinterstitial fluids. For this purpose, patients with a history ofhyponatremia are treated either with a pharmaceutical compositionaccording to the invention or with placebo or with a non-drug therapy orwith other medicaments, over a short period (e.g. 3 to 6 months), withperiodic assessment of serum sodium levels. An increase in sodium levelsinto the normal range reported during this time period when treated witha pharmaceutical composition according to the invention compared with adifferent type of therapy, is proof of the efficacy of a pharmaceuticalcomposition in treating hyponatremia.

Example 14 Treatment/Prevention of Kidney Stones

Patients with a history of kidney stones, particularly calcium, mixedcalcium, and uric acid stones frequently have a history ofhyperuricemia. These renal stones may relate to small urate crystalsforming a nidus in the renal filtrate upon which further crystalizationof urate or other crystalizing substances in the solute can induce renalstone formation. These stones are not related to renal stones caused bycertain kidney infections (such as staghorn—type stones). Therapy may beprovided with the objective of increasing the neutral solutes (forexample glucose) and free water content of the renal filtrate, making itdifficult for a urate nidus to form, despite a possible increase in theabsolute amounts of urate in the renal filtrate. These neutral solutesand free water will also reduce the formation of stones other than uricacid stones. For this purpose patients with a history of kidney stonesparticularly calcium, mixed calcium, and uric acid stones are treatedeither with a pharmaceutical composition according to the invention orwith placebo or with a non-drug therapy or with other medicaments, overa lengthy period (e.g. 6 months to 4 years). A reduction in the numberof kidney stones stones particularly calcium, mixed calcium, and uricacid stones reported during this time period when treated with apharmaceutical composition according to the invention compared with adifferent type of therapy, is proof of the efficacy of a pharmaceuticalcomposition in preventing kidney stones particularly calcium, mixedcalcium, and uric acid stones.

Example 15 Body Weight and Body Fat Reduction

The following example shows the beneficial effect of the compound (I.9)on body weight and total body fat content. All experimental proceduresconcerning the use of laboratory animals were carried out under a HomeOffice Certificate of Designation. An animal model of obesity was usedto study the effect of the compound (I.9) on body weight and total bodyfat content. For this, female Wistar rats were made obese by exposure toa simplified cafeteria diet containing high fat chow, chocolate andground peanuts for approximately 24 weeks. Following the induction ofobesity, rats were given vehicle (0.5% aqueous hydroxyethyl-cellulose)for 7 days and then dosed orally once daily with either vehicle or 3mg/kg or 10 mg/kg compound (I.9) for 28 days. For the duration of thestudy rats were maintained on the cafeteria diet. Body weight wasmonitored daily and the final body weight after 28 day treatment isgiven in the FIG. 4A. Therein “Cpd A” denotes theglucopyranosyl-substituted benzene derivative (I.9) at a dose of 3 mg/kgor 10 mg/kg. Results are means (adjusted for differences between thebody weights of the different treatment groups at baseline (Day 1))±SEM(calculated from the residuals of the statistical model), n=10. After 28day daily oral treatment with the compound (I.9) a reduced body weightcompared to the vehicle-treated control group was observed. Body weightdata was analysed by analysis of covariance with body weights on Day 1as covariate. P values versus vehicle control are indicated by symbolsabove the bars (*, p<0.05) Multiple comparisons against the vehiclecontrol group were performed by Williams' test for the twofreely-feeding “Cpd A” groups. The glucopyranosyl-substituted benzenederivative (1.9) reduced the body weight by 4.1% at 3 mg/kg andsignificantly by 6.9% at 10 mg/kg.

At the end of the study on Day 34 (24 hours after the last treatment onDay 33) all rats were terminated, the body exsanguinated and thefollowing tissues removed: the caudate liver lobe, the pancreas, theleft kidney and one soleus muscle. Body composition (body fat, proteinand water) was determined using the FoodScan NIR (near infra-red) meatanalyser (Foss UK). This machine has AOAC (Association of OfficialAnalytical Chemists) approval as reference method for the analysis ofmoisture, fat and protein in meat. The carcasses were milled underliquid nitrogen and a portion of the milled carcass was analysed in theFoodScan Analyser. The results of the determination of body fat contentare given in FIG. 4B. Therein “Cpd A” denotes theglucopyranosyl-substituted benzene derivative (I.9) at a dose of 3 mg/kgor 10 mg/kg. After 33 day daily oral treatment with the compound (I.9) areduced body fat content compared to the control group was observed.Means (n=9-10) are adjusted for differences between treatment groups inbody weight at baseline (Day 1). Carcasses from all animals wereanalysed less terminal bleeds (exsanguination), pancreas and caudatelobe of the liver whilst 4-5 animals per group additionally had the leftkidney and one soleus muscle removed. Statistical analysis was by robustregression and included Day 1 body weight as a covariate. Standarderrors of the mean (SEM) are calculated from the residuals of thestatistical model. Comparisons against the vehicle-treated control groupon the cafeteria diet were by Williams' tests for the freely feeding“Cpd A” animals (3 mg/kg and 10 mg/kg). Significant differences aredenoted by *p<0.05. The total body fat content (expressed as weight perrat) was significantly lower after treatment with 10 mg/kg of thecompound (1.9) in comparison to vehicle-treated animals.

Examples of Formulations

The following examples of formulations, which may be obtainedanalogously to methods known in the art, serve to illustrate the presentinvention more fully without restricting it to the contents of theseexamples. The term “active substance” denotes a SGLT-2 inhibitoraccording to this invention, especially a compound of the formula (I),for example a compound of the formula (I.9) or its crystalline form(I.9X).

The active pharmaceutical ingredient or active sustance, i.e. thecompound (I.9), preferably in the crystalline form (I9.X), is milledwith a suitable mill like pin- or jet-mill in order to obtain thedesired particle size distribution before manufacturing of thepharmaceutical composition or dosage form.

Examples of typical particle size distribution values X90, X50 and X10for the preferred active pharmaceutical ingredient according to theinvention are shown in the table below.

Typical particle size distribution results

Active Active substance substance Batch 1 Batch 2 X10  1.8 μm  1.7 μmX50 18.9 μm 12.1 μm X90 45.3 μm 25.9 μm

Example 1 Dry Ampoule Containing 50 mg of Active Substance Per 10 mlComposition

Active substance 50.0 mg Mannitol 50.0 mg water for injections ad 10.0ml

Preparation:

Active substance and mannitol are dissolved in water. After packagingthe solution is freeze-dried. To produce the solution ready for use, theproduct is dissolved in water for injections.

Example 2 Dry Ampoule Containing 25 mg of Active Substance Per 2 mlComposition

Active substance 25.0 mg Mannitol 100.0 mg water for injections ad 2.0ml

Preparation:

Active substance and mannitol are dissolved in water. After packaging,the solution is freeze-dried. To produce the solution ready for use, theproduct is dissolved in water for injections.

Example 3 Tablet Containing 50 mg of Active Substance Composition

(1) Active substance 50.0 mg (2) Mannitol 98.0 mg (3) Maize starch 50.0mg (4) Polyvinylpyrrolidone 15.0 mg (5) Magnesium stearate  2.0 mg 215.0mg 

Preparation:

(1), (2) and (3) are mixed together and granulated with an aqueoussolution of (4). (5) is added to the dried granulated material. Fromthis mixture tablets are pressed, biplanar, faceted on both sides andwith a dividing notch on one side.

Diameter of the tablets: 9 mm.

Example 4 Capsules Containing 50 mg of Active Substance Composition

(1) Active substance 50.0 mg (2) Dried maize starch 58.0 mg (3) Mannitol50.0 mg (4) Magnesium stearate  2.0 mg 160.0 mg 

Preparation:

(1) is triturated with (3). This trituration is added to the mixture of(2) and (4) with vigorous mixing. This powder mixture is packed intosize 3 hard gelatin capsules in a capsule filling machine.

Example 5 Tablets Containing 2.5mg, 5mg, 10mg, 25mg, 50mg of ActiveSubstance

2.5 mg 5 mg 10 mg 25 mg 50 mg Mg/per Mg/per Mg/per Mg/per Mg/per Activesubstance tablet tablet tablet tablet tablet Wet granulation activesubstance 2.5000 5.000 10.00 25.00 50.00 Lactose 40.6250 81.250 162.50113.00 226.00 Monohydrate Microcrystalline 12.5000 25.000 50.00 40.0080.00 Cellulose Hydroxypropyl 1.8750 3.750 7.50 6.00 12.00 CelluloseCroscarmellose 1.2500 2.500 5.00 4.00 8.00 Sodium Purified Water q.s.q.s. q.s. q.s. q.s. Dry Adds Microcrystalline 3.1250 6.250 12.50 10.0020.00 Cellulose Colloidal silicon 0.3125 0.625 1.25 1.00 2.00 dioxideMagnesium stearate 0.3125 0.625 1.25 1.00 2.00 Total core 62.5000125.000 250.00 200.00 400.00 Film Coating Film coating system 2.50004.000 7.00 6.00 9.00 Purified Water q.s. q.s. q.s. q.s. q.s. Total65.000 129.000 257.00 206.00 409.00

Example 6

Manufacturing Process for Tablets

Example 7 Pharmaceutical Composition Containing Other Fillers

Copovidone is dissolved in purified water at ambient temperature toproduce a granulation liquid. A glucopyranosyl-substituted benzenederivative according to the present invention, mannitol, pregelatinizedstarch and corn starch are blended in a suitable mixer, to produce apre-mix. The pre-mix is moistened with the granulation liquid andsubsequently granulated. The moist granulate is sieved through asuitable sieve. The granulate is dried at about 60° C. inlet airtemperature in a fluid bed dryer until a loss on drying value of 1-4% isobtained. The dried granulate is sieved through a sieve with a mesh sizeof 1.0 mm.

Magnesium stearate is passed through a sieve for delumping and added tothe granulate. Subsequently the final blend is produced by finalblending in a suitable blender for three minutes and compressed intotablet cores.

Hydroxypropyl methylcellulose, polyethylene glycol, talc, titaniumdioxide and iron oxide are suspended in purified water in a suitablemixer at ambient temperature to produce a coating suspension. The tabletcores are coated with the coating suspension to a weight gain of about3% to produce film-coated tablets. The following formulation variantscan be obtained:

mg/ mg/ mg/ mg/ mg/ Ingredient tablet tablet tablet tablet tablet Activesubstance 2.5 5.0 10.0 25.0 50.0 Mannitol 133.4 130.9 125.9 110.9 221.8Pregelatinised starch 18.0 18.0 18.0 18.0 36.0 Maize starch 18.0 18.018.0 18.0 36.0 Copovidone 5.4 5.4 5.4 5.4 10.8 Magnesium stearate 2.72.7 2.7 2.7 5.4 Film coat 5.0 5.0 5.0 5.0 10.0 Total 185.0 185.0 185.0185.0 370.0

Example 8 Pharmaceutical Composition Containg Other Disintegrant

Copovidone is dissolved in purified water at ambient temperature toproduce a granulation liquid. An glucopyranosyl-substituted benzenederivative according to the present invention, mannitol, pregelatinizedstarch and corn starch are blended in a suitable mixer, to produce apre-mix. The pre-mix is moistened with the granulation liquid andsubsequently granulated. The moist granulate is sieved through asuitable sieve. The granulate is dried at about 60° C. inlet airtemperature in a fluid bed dryer until a loss on drying value of 1-4% isobtained. The dried granulate is sieved through a sieve with a mesh sizeof 1.0 mm.

Crospovidone is added to the dried granulate and mixed for 5 minutes toproduce the main blend. Magnesium stearate is passed through a sieve fordelumping and added to main blend. Subsequently the final blend isproduced by final blending in a suitable blender for three minutes andcompressed into 8 mm round tablet cores with a compression force of 16kN.

Hydroxypropyl methylcellulose, polyethylene glycol, talc, titaniumdioxide and iron oxide are suspended in purified water in a suitablemixer at ambient temperature to produce a coating suspension. The tabletcores are coated with the coating suspension to a weight gain of about3% to produce film-coated tablets. The following formulation variantscan be obtained:

mg/ mg/ mg/ mg/ mg/ Ingredient tablet tablet tablet tablet tablet Activesubstance 2.5 5.0 10.0 25.0 50.0 Mannitol 127.5 125.0 120.0 105.0 210.0Microcrystalline Cellulose 39.0 39.0 39.0 39.0 78.0 Crospovidone 2.0 2.02.0 2.0 4.0 Copovidone 5.4 5.4 5.4 5.4 10.8 Magnesium stearate 3.6 3.63.6 3.6 7.2 Film coat 5.0 5.0 5.0 5.0 10.0 Total 185.0 185.0 185.0 185.0370.0

The tablet hardness, the friability, the content uniformity, thedisintegration time and the dissolution properties are determined asdescribed hereinbefore.

Example 9 Direct Compression Formulation

1. Screen the active ingredient, microcrystalline cellulose,croscarmellose.sodium and either hydroxypropyl cellulose or polyethyleneglycol powder through a 20 mesh hand screen.

2. Add the above items into the high shear mixer and mix for twominutes.

3. Make a premix (˜1/1) of the lactose and colloidal silicon dioxide.

4. Screen the premix through a 20 mesh hand screen and add to the mixer.

5. Screen the remaining lactose through a 20 mesh hand screen and add tothe mixer.

6. Mix in components in the mixer for 2 minutes.

7. Screen the magnesium stearate through a 30 mesh hand screen and addto the mixer.

8. Mix for 1 minute 30 seconds to obtain the final blend.

9 Tabletting of the final blend on a suitable tabletting press.

10. Optionally film coating of the tablet cores.

mg/ mg/ mg/ mg/ mg/ Ingredient tablet tablet tablet tablet tablet Activesubstance 2.5000 5.000 10.00 25.0 50.0 Lactose Monohydrate 43.750087.500 175.00 74.0 148.0 Microcrystalline 12.5000 25.000 50.00 80.0160.0 Cellulose Polyethylene glycol — — — 10.0 20.0 Croscarmellosesodium 1.2500 2.500 5.00 8.0 16.0 Hydroxypropyl cellulose 1.8750 3.7507.50 — — Colloidal Silicon dioxide 0.3125 0.625 1.25 1.0 2.0 Magnesiumstearate 0.3125 0.625 1.25 2.0 4.0 Film coat 2.5000 4.000 7.00 6.00 9.00Purified water q.s. q.s. q.s. q.s. q.s. Total 65.000 129.000 257.00206.00 409.00

Example 10 Tablets Containing 0.5mg, 5mg, 25mg, 100mg of ActiveSubstance

100 mg 0.5 mg 5 mg 25 mg mg/per Active substance mg/per tablet mg/pertablet mg/per tablet tablet Wet granulation active substance 2.50005.000 25.00 100.00 Lactose 60.00 55.00 42.00 168.00 MonohydrateMicrocrystalline 20.00 20.00 38.00 152.00 Cellulose Hydroxypropyl 5.005.00 7.50 30.00 Cellulose Croscarmellose 4.00 4.00 6.00 24.00 SodiumPurified Water q.s. q.s. q.s. q.s. Dry Adds Microcrystalline 10.00 10.0030.00 120.00 Cellulose Colloidal silicon — 0.50 0.75 3.00 dioxideMagnesium stearate 0.50 0.50 0.75 3.00 Total 100.00 100.00 150.00 600.00

The active substance, e.g. the compound (I.9), preferably in thecrystalline form (I.9X), hydroxypropyl cellulose, and croscarmellosesodium are mixed in a blender. This premix is mixed with lactosemonohydrate and a portion of microcrystalline cellulose. The resultingblend is granulated with purified water. Multiple granulation subpartsmay be produced for an individual tablet batch, as needed, depending onthe batch size and equipment used. The granulation is discharged ontodryer trays and dried. The granulation is then milled. The remainder ofthe microcrystalline cellulose is added (as a premix with the colloidalsilicon dioxide for all strengths other than the 0.5 mg) to the milledgranulation, and mixed. The magnesium stearate is premixed with aportion of the blend, screened into the remainder of the granulation,and mixed.

The final tablet blend is compressed into tablets using a tablet press.The finished tablets are packaged using a suitable container closuresystem.

Example 11 Tablets Containing 1 mg, 5mg, 25mg of Active Substance

1 mg 5 mg 25 mg Active substance mg/per tablet mg/per tablet mg/pertablet Wet granulation active substance 1.00 5.00 25.00 Lactose 63.0059.00 39.00 Monohydrate Microcrystalline 20.00 20.00 20.00 CelluloseHydroxypropyl 3.00 3.00 3.00 Cellulose Croscarmellose 2.00 2.00 2.00Sodium Purified Water q.s. q.s. q.s. Dry Adds Microcrystalline 10.0010.00 10.00 Cellulose Colloidal silicon 0.50 0.50 0.50 dioxide Magnesiumstearate 0.50 0.50 0.50 Total 100.00 100.00 100.00

The active substance, e.g. the compound (I.9), preferably in thecrystalline form (I.9X), is passed through a screen and added to ablender or a high shear granulator. The hydroxypropyl cellulose andcroscarmellose sodium are passed through a screen, added to the drugsubstance, and mixed. The intra-granular portion of microcrystallinecellulose is passed through a screen into a high shear granulator andmixed with the drug substance premix. Lactose is then added by passingthe material through a screen into the granulator and mixing. Theresulting blend is granulated with purified water. For larger batches,multiple granulation subparts may be produced for an individual tabletbatch, as needed, depending on the batch size and equipment used.

The granulation is discharged onto dryer trays and dried. Thegranulation is then passed through a mill into a blender. The colloidalsilicon dioxide is pre-mixed with a portion of the extra-granularmicrocrystalline cellulose. This premix is passed through a mill intothe blender, followed by the remaining extra-granular microcrystallinecellulose, and mixed with the milled granulation. The magnesium stearateis premixed with a portion of the blend, passed through a mill into theremainder of the granulation, and mixed. The final tablet blend iscompressed into tablets using a tablet press. The finished tablets arepackaged using a suitable container closure system.

Examples of Tests with Regard to Properties of PharmaceuticalCompositions and Pharmaceutical Dosage Forms

1. Disintegration Test

Disintegration test was performed as described in USP31-NF26 S2, chapter701 (disintegration).

2. Dissolution Test

The standard dissolution test is described in USP31-NF26 S2, chapter 711(dissolution). The paddle method (Apparatus 2) with an agitation speedof 50 rpm was used. The dissolution media is 900 mL 0.05 M Potassiumphosphate buffer pH 6.8 at a temperature of 37° C. Samples are takenafter 10, 15, 20, 30 and 45 minutes. The samples are analyzed via HPLC.

3. Particle Size Distribution Measurement by Laser Diffraction

Particle size distribution measurement is performed for example vialight scattering or laser diffraction technique. To determine theparticle size the powder is fed into a laser diffraction spectrometerfor example by means of a dispersing unit. The test method is describedbelow in detail:

Equipment: Laser Diffraction Spectrometer Sympatec HELOS Particle Sizer.Lens: R31 (0.5/0.9 μm-175 μm) Sample Dispersing Unit: Dry disperserRODOS/M Vacuum: Nilfisk Feeder: ASPIROS Feed Velocity: 60.00 mm/sPrimary pressure: 2.00 bar Injector depression: maximize (mbar)2Reference Measurement: 10 seconds Cycle Time: 100 msec TriggerConditions: Start 0.0 seconds after optical concentration ≥1% validalways Stop after 5.0 seconds optical concentration ≤1% or after 30seconds real time Optical Concentration: Approximately range 3-12%Evaluation: HRLD Sample Size: Approximately 100 mg Number ofmeasuremtns: 2 (duplicate)

The instrument is set up according to the manufacturer's recommendationand using the manufacturer provided software. The sample container isthoroughly mixed and tumbled prior to removing a portion of the sampleto ensure that a representative sample is tested. Duplicate samples areprepared by using a spatula to transfer approximately 100 mg of a sampleinto the ASPIROS glass vials and cap the vials. The capped cials areplaced into the feeder.

4. Tablet Hardness and Friability

Tablet hardness and friability test was performed as described inUSP31-NF26 S2, chapter 1217 (tablet breaking force).

1. Method for preventing, slowing the progression of, delaying ortreating a metabolic disorder selected from the group consisting of type1 diabetes mellitus, type 2 diabetes mellitus, impaired glucosetolerance, impaired fasting blood glucose, hyperglycemia, postprandialhyperglycemia, overweight, obesity, metabolic syndrome, gestationaldiabetes, new onset diabetes after transplantation (NODAT) andcomplications associated therewith, and post-transplant metabolicsyndrome (PTMS) and complications associated therewith in a patient inneed thereof characterized in that a pharmaceutical compositioncomprising an SGLT2 inhibitor is administered to the patient, whereinthe SGLT2 inhibitor is a glucopyranosyl-substituted benzene derivativeof the formula (I)

wherein R¹ denotes Cl, methyl or cyano; R² denotes H, methyl, methoxy orhydroxy and R³ denotes ethyl, cyclopropyl, ethynyl, ethoxy,(R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy; or a prodrugthereof.
 2. Method according to claim 1 wherein the patient: (1) is anindividual diagnosed of one or more of the conditions selected from thegroup consisting of overweight, obesity, visceral obesity and abdominalobesity; or (2) is an individual who shows one, two or more of thefollowing conditions: (a) a fasting blood glucose or serum glucoseconcentration greater than 100 mg/dL, in particular greater than 125mg/dL; (b) a postprandial plasma glucose equal to or greater than 140mg/dL; (c) an HbA1c value equal to or greater than 6.5%, in particularequal to or greater than 8.0%; or (3) is an individual wherein one, two,three or more of the following conditions are present: (a) obesity,visceral obesity and/or abdominal obesity, (b) triglyceride blood level≥150 mg/dL, (c) HDL-cholesterol blood level <40 mg/dL in female patientsand <50 mg/dL in male patients, (d) a systolic blood pressure ≥130 mm Hgand a diastolic blood pressure ≥85 mm Hg, (e) a fasting blood glucoselevel ≥100 mg/dL.
 3. Method according to claim 1, wherein the SGLT2inhibitor is selected from the group consisting of the group ofcompounds (I.1) to (I.11): (I.1)6-(4-ethylbenzyl)-4-(β-D-glucopyranos-1-yl)-2-methoxy-benzonitrile,(I.2)2-(4-ethylbenzyl)-4-(β-D-glucopyranos-1-yl)-5-methoxy-benzonitrile,(I.3)1-cyano-2-(4-ethylbenzyl)-4-(β-D-glucopyranos-1-yl)-5-methyl-benzene,(I.4)2-(4-ethylbenzyl)-4-(β-D-glucopyranos-1-yl)-5-hydroxy-benzonitrile,(I.5) 2-(4-ethyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzonitrile, (I.6)2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzonitrile, (I.7)1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-ethynyl-benzyl)-benzene, (I.8)1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((R)-tetrahydrofuran-3-yloxy)-benzyl]-benzene,(I.9)1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene,(I.10)1-methyl-2-[4-((R)-tetrahydrofuran-3-yloxy)-benzyl]-4-(β-D-glucopyranos-1-yl)-benzene,and (I.11)1-methyl-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-4-(β-D-glucopyranos-1-yl)-benzene.4. Method according to claim 1 wherein the pharmaceutical compositionadditionally comprises one or more pharmaceutically acceptable carriers.5. Method for improving glycemic control and/or for reducing of fastingplasma glucose, of postprandial plasma glucose and/or of glycosylatedhemoglobin HbA1c in a patient in need thereof characterized in that apharmaceutical composition comprising an SGLT2 is administered to thepatient, wherein the SGLT2 inhibitor is a glucopyranosyl-substitutedbenzene derivative of the formula (I)

wherein R¹ denotes Cl, methyl or cyano; R² denotes H, methyl, methoxy orhydroxy and R³ denotes ethyl, cyclopropyl, ethynyl, ethoxy,(R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy; or a prodrugthereof.
 6. Method according to claim 5 wherein the patient: (1) is anindividual diagnosed of one or more of the conditions selected from thegroup consisting of overweight, obesity, visceral obesity and abdominalobesity; or (2) is an individual who shows one, two or more of thefollowing conditions: (a) a fasting blood glucose or serum glucoseconcentration greater than 100 mg/dL, in particular greater than 125mg/dL; (b) a postprandial plasma glucose equal to or greater than 140mg/dL; (c) an HbA1c value equal to or greater than 6.5%, in particularequal to or greater than 8.0%; or (3) is an individual wherein one, two,three or more of the following conditions are present: (a) obesity,visceral obesity and/or abdominal obesity, (b) triglyceride blood level≥150 mg/dL, (c) HDL-cholesterol blood level <40 mg/dL in female patientsand <50 mg/dL in male patients, (d) a systolic blood pressure ≥130 mm Hgand a diastolic blood pressure ≥85 mm Hg, (e) a fasting blood glucoselevel ≥100 mg/dL.
 7. Method according to claim 5, wherein the SGLT2inhibitor is selected from the group consisting of the group ofcompounds (I.1) to (I.11): (I.1)6-(4-ethylbenzyl)-4-(β-D-glucopyranos-1-yl)-2-methoxy-benzonitrile,(I.2)2-(4-ethylbenzyl)-4-(β-D-glucopyranos-1-yl)-5-methoxy-benzonitrile,(I.3)1-cyano-2-(4-ethylbenzyl)-4-(β-D-glucopyranos-1-yl)-5-methyl-benzene,(I.4)2-(4-ethylbenzyl)-4-(β-D-glucopyranos-1-yl)-5-hydroxy-benzonitrile,(1.5) 2-(4-ethyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzonitrile, (I.6)2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzonitrile, (I.7)1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-ethynyl-benzyl)-benzene, (I.8)1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((R)-tetrahydrofuran-3-yloxy)-benzyl]-benzene,(I.9)1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene,(I.10)1-methyl-2-[4-((R)-tetrahydrofuran-3-yloxy)-benzyl]-4-(β-D-glucopyranos-1-yl)-benzene,and (I.11)1-methyl-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-4-(β-D-glucopyranos-1-yl)-benzene.8. Method according to claim 5 wherein the pharmaceutical compositionadditionally comprises one or more pharmaceutically acceptable carriers.9. Method for preventing, slowing, delaying or reversing progressionfrom impaired glucose tolerance, impaired fasting blood glucose, insulinresistance and/or from metabolic syndrome to type 2 diabetes mellitus ina patient in need thereof characterized in that a pharmaceuticalcomposition comprising an SGLT2 inhibitor is administered to thepatient, wherein the SGLT2 inhibitor is a glucopyranosyl-substitutedbenzene derivative of the formula (I)

wherein R¹ denotes Cl, methyl or cyano; R² denotes H, methyl, methoxy orhydroxy and R³ denotes ethyl, cyclopropyl, ethynyl, ethoxy,(R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy; or a prodrugthereof.
 10. Method according to claim 9 wherein the patient: (1) is anindividual diagnosed of one or more of the conditions selected from thegroup consisting of overweight, obesity, visceral obesity and abdominalobesity; or (2) is an individual who shows one, two or more of thefollowing conditions: (a) a fasting blood glucose or serum glucoseconcentration greater than 100 mg/dL, in particular greater than 125mg/dL; (b) a postprandial plasma glucose equal to or greater than 140mg/dL; (c) an HbA1c value equal to or greater than 6.5%, in particularequal to or greater than 8.0%; or (3) is an individual wherein one, two,three or more of the following conditions are present: (a) obesity,visceral obesity and/or abdominal obesity, (b) triglyceride blood level≥150 mg/dL, (c) HDL-cholesterol blood level <40 mg/dL in female patientsand <50 mg/dL in male patients, (d) a systolic blood pressure ≥130 mm Hgand a diastolic blood pressure ≥85 mm Hg, (e) a fasting blood glucoselevel ≥100 mg/dL.
 11. Method according to claim 9, wherein the SGLT2inhibitor is selected from the group consisting of the group ofcompounds (I.1) to (I.11): (I.1)6-(4-ethylbenzyl)-4-(β-D-glucopyranos-1-yl)-2-methoxy-benzonitrile,(I.2)2-(4-ethylbenzyl)-4-(β-D-glucopyranos-1-yl)-5-methoxy-benzonitrile,(I.3) 1-cyano-2-(4-ethylbenzyl)-4-(β-D-glucopyranos-1-yl)-5-methyl-benzene, (I.4)2-(4-ethylbenzyl)-4-(β-D-glucopyranos-1-yl)-5-hydroxy-benzonitrile,(I.5) 2-(4-ethyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzonitrile, (I.6)2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzonitrile, (I.7)1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-ethynyl-benzyl)-benzene, (I.8)1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((R)-tetrahydrofuran-3-yloxy)-benzyl]-benzene,(I.9)1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene,(I.10)1-methyl-2-[4-((R)-tetrahydrofuran-3-yloxy)-benzyl]-4-(β-D-glucopyranos-1-yl)-benzene,and (I.11)1-methyl-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-4-(β-D-glucopyranos-1-yl)-benzene.12. Method according to claim 9 wherein the pharmaceutical compositionadditionally comprises one or more pharmaceutically acceptable carriers.13. Method for preventing, slowing the progression of, delaying ortreating of a condition or disorder selected from the group consistingof complications of diabetes mellitus such as cataracts and micro- andmacrovascular diseases, such as nephropathy, retinopathy, neuropathy,tissue ischaemia, diabetic foot, arteriosclerosis, myocardialinfarction, accute coronary syndrome, unstable angina pectoris, stableangina pectoris, stroke, peripheral arterial occlusive disease,cardiomyopathy, heart failure, heart rhythm disorders and vascularrestenosis, in a patient in need thereof characterized in that apharmaceutical composition comprising an SGLT2 inhibitor is administeredto the patient, wherein the SGLT2 inhibitor is aglucopyranosyl-substituted benzene derivative of the formula (I)

wherein R¹ denotes Cl, methyl or cyano; R² denotes H, methyl, methoxy orhydroxy and R³ denotes ethyl, cyclopropyl, ethynyl, ethoxy,(R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy; or a prodrugthereof.
 14. Method according to claim 13 wherein the patient: (1) is anindividual diagnosed of one or more of the conditions selected from thegroup consisting of overweight, obesity, visceral obesity and abdominalobesity; or (2) is an individual who shows one, two or more of thefollowing conditions: (a) a fasting blood glucose or serum glucoseconcentration greater than 100 mg/dL, in particular greater than 125mg/dL; (b) a postprandial plasma glucose equal to or greater than 140mg/dL; (c) an HbA1c value equal to or greater than 6.5%, in particularequal to or greater than 8.0%; or (3) is an individual wherein one, two,three or more of the following conditions are present: (a) obesity,visceral obesity and/or abdominal obesity, (b) triglyceride blood level≥150 mg/dL, (c) HDL-cholesterol blood level <40 mg/dL in female patientsand <50 mg/dL in male patients, (d) a systolic blood pressure ≥130 mm Hgand a diastolic blood pressure ≥85 mm Hg, (e) a fasting blood glucoselevel ≥100 mg/dL.
 15. Method according to claim 13, wherein the SGLT2inhibitor is selected from the group consisting of the group ofcompounds (I.1) to (I.11): (I.1)6-(4-ethylbenzyl)-4-(β-D-glucopyranos-1-yl)-2-methoxy-benzonitrile,(I.2)2-(4-ethylbenzyl)-4-(β-D-glucopyranos-1-yl)-5-methoxy-benzonitrile,(I.3)1-cyano-2-(4-ethylbenzyl)-4-(β-D-glucopyranos-1-yl)-5-methyl-benzene,(I.4)2-(4-ethylbenzyl)-4-(β-D-glucopyranos-1-yl)-5-hydroxy-benzonitrile,(I.5) 2-(4-ethyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzonitrile, (I.6)2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzonitrile, (I.7)1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-ethynyl-benzyl)-benzene, (I.8)1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((R)-tetrahydrofuran-3-yloxy)-benzyl]-benzene,(I.9)1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene,(I.10)1-methyl-2-[4-((R)-tetrahydrofuran-3-yloxy)-benzyl]-4-(β-D-glucopyranos-1-yl)-benzene,and (I.11)1-methyl-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-4-(β-D-glucopyranos-1-yl)-benzene.16. Method according to claim 13 wherein the pharmaceutical compositionadditionally comprises one or more pharmaceutically acceptable carriers.17. Method for reducing body weight and/or body fat, or preventing anincrease in body weight and/or body fat, or facilitating a reduction inbody weight and/or body fat, in a patient in need thereof characterizedin that a pharmaceutical composition comprising an SGLT2 inhibitor isadministered to the patient, wherein the SGLT2 inhibitor is aglucopyranosyl-substituted benzene derivative of the formula (I)

wherein R¹ denotes Cl, methyl or cyano; R² denotes H, methyl, methoxy orhydroxy and R³ denotes ethyl, cyclopropyl, ethynyl, ethoxy,(R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy; or a prodrugthereof.
 18. Method according to claim 17 wherein the patient: (1) is anindividual diagnosed of one or more of the conditions selected from thegroup consisting of overweight, obesity, visceral obesity and abdominalobesity; or (2) is an individual who shows one, two or more of thefollowing conditions: (a) a fasting blood glucose or serum glucoseconcentration greater than 100 mg/dL, in particular greater than 125mg/dL; (b) a postprandial plasma glucose equal to or greater than 140mg/dL; (c) an HbA1c value equal to or greater than 6.5%, in particularequal to or greater than 8.0%; or (3) is an individual wherein one, two,three or more of the following conditions are present: (a) obesity,visceral obesity and/or abdominal obesity, (b) triglyceride blood level≥150 mg/dL, (c) HDL-cholesterol blood level <40 mg/dL in female patientsand <50 mg/dL in male patients, (d) a systolic blood pressure >130 mm Hgand a diastolic blood pressure ≥85 mm Hg, (e) a fasting blood glucoselevel ≥100 mg/dL.
 19. Method according to claim 17, wherein the SGLT2inhibitor is selected from the group consisting of the group ofcompounds (I.1) to (I.11): (I.1)6-(4-ethylbenzyl)-4-(β-D-glucopyranos-1-yl)-2-methoxy-benzonitrile,(I.2) 2-(4-ethylbenzyl)-4-(βD-glucopyranos-1-yl)-5-methoxy-benzonitrile,(I.3) 1-cyano-2-(4-ethylbenzyl)-4-(βD-glucopyranos- 1-yl)-5-methyl-benzene, (I.4)2-(4-ethylbenzyl)-4-(βD-glucopyranos-1-yl)-5-hydroxy-benzonitrile, (I.5)2-(4-ethyl-benzyl)-4-(βD-glucopyranos-1-yl)-benzonitrile, (I.6)2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzonitrile, (I.7)1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-ethynyl-benzyl)-benzene, (I.8)1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((R)-tetrahydrofuran-3-yloxy)-benzyl]-benzene, (I.9)1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene, (I.10)1-methyl-2-[4-((R)-tetrahydrofuran-3-yloxy)-benzyl]-4-(β-D-glucopyranos-1-yl)-benzene,and (I.11)1-methyl-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-4-(β-D-glucopyranos-1-yl)-benzene.20. Method according to claim 17 wherein the pharmaceutical compositionadditionally comprises one or more pharmaceutically acceptable carriers.21.-36. (canceled)